Skip to main content

Advertisement

SpringerLink
Log in

MHC heterogeneity and response of metastases to immunotherapy

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

In recent years, immunotherapy has proven to be an effective treatment against cancer. Cytotoxic T lymphocytes perform an important role in this anti-tumor immune response, recognizing cancer cells as foreign, through the presentation of tumor antigens by MHC class I molecules. However, tumors and metastases develop escape mechanisms for evading this immunosurveillance and may lose the expression of these polymorphic molecules to become invisible to cytotoxic T lymphocytes. In other situations, they may maintain MHC class I expression and promote immunosuppression of cytotoxic T lymphocytes. Therefore, the analysis of the expression of MHC class I molecules in tumors and metastases is important to elucidate these escape mechanisms. Moreover, it is necessary to determine the molecular mechanisms involved in these alterations to reverse them and recover the expression of MHC class I molecules on tumor cells. This review discusses the role and regulation of MHC class I expression in tumor progression. We focus on altered MHC class I phenotypes present in tumors and metastases, as well as the molecular mechanisms responsible for MHC-I alterations, emphasizing the mechanisms of recovery of the MHC class I molecules expression on cancer cells. The individualized study of the HLA class I phenotype of the tumor and the metastases of each patient will allow choosing the most appropriate immunotherapy treatment based on a personalized medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gorer, P. A. (1936). The detection of antigenic differences in mouse erythrocytes by the employment of immune Sera. British Journal of Experimental Pathology, 17(1), 42–50 Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2065193/.

    CAS  PubMed Central  Google Scholar 

  2. Dausset, J. (1952). The agglutination mechanism of trypsin modified red cells. Blood, 7(8), 816–825. https://doi.org/10.1182/blood.V7.8.816.816.

    Article  CAS  PubMed  Google Scholar 

  3. Bjorkman, P. J., & Parham, P. (1990). Structure, function, and diversity of class I major histocompatibility complex molecules. Annual Review of Biochemistry, 59, 253–288. https://doi.org/10.1146/annurev.bi.59.070190.001345.

    Article  CAS  PubMed  Google Scholar 

  4. Le Bouteiller, P. (2017). HLA Class I chromosomal region, genes, and products: Facts and questions. Critical Reviews in Immunology, 37(2–6), 317–357. https://doi.org/10.1615/CritRevImmunol.v37.i2-6.80.

    Article  PubMed  Google Scholar 

  5. Leone, P., Shin, E.-C., Perosa, F., Vacca, A., Dammacco, F., & Racanelli, V. (2013). MHC class I antigen processing and presenting machinery: Organization, function, and defects in tumor cells. Journal of the National Cancer Institute, 105(16), 1172–1187. https://doi.org/10.1093/jnci/djt184.

    Article  CAS  PubMed  Google Scholar 

  6. Garrido, F., & Algarra, I. (2001). MHC antigens and tumor escape from immune surveillance. In In Advances in Cancer Research (83rd ed., pp. 117–158). Academic Press. https://doi.org/10.1016/S0065-230X(01)83005-0.

  7. Daar, A. S., Fuggle, S. V., Fabre, J. W., Ting, A., & Morris, P. J. (1984). The detailed distribution of MHC class II antigens in normal human organs. Transplantation, 38(3), 293–298. https://doi.org/10.1097/00007890-198409000-00019.

    Article  CAS  PubMed  Google Scholar 

  8. Janeway, C. A., Bottomly, K., Horowitz, J., Kaye, J., Jones, B., & Tite, J. (1985). Modes of cell:cell communication in the immune system. Journal of Immunology, 135(2 Suppl), 739s–742s Retrieved from http://europepmc.org/abstract/MED/3159798.

    Google Scholar 

  9. Arnold, P. Y., La Gruta, N. L., Miller, T., Vignali, K. M., Adams, P. S., Woodland, D. L., & Vignali, D. A. A. (2002). The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues. Journal of Immunology, 169(2), 739–749. https://doi.org/10.4049/jimmunol.169.2.739.

    Article  CAS  Google Scholar 

  10. Madsen, L., Labrecque, N., Engberg, J., Dierich, A., Svejgaard, A., Benoist, C., Mathis, D., & Fugger, L. (1999). Mice lacking all conventional MHC class II genes. Proceedings of the National Academy of Sciences of the United States of America, 96(18), 10338–10343. https://doi.org/10.1073/pnas.96.18.10338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thibodeau, J., Bourgeois-Daigneault, M.-C., & Lapointe, R. (2012). Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology, 1(6), 908–916. https://doi.org/10.4161/onci.21205.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Garrido, F., Algarra, I., & García-Lora, A. M. (2010). The escape of cancer from T lymphocytes: Immunoselection of MHC class I loss variants harboring structural-irreversible “hard” lesions. Cancer Immunology, Immunotherapy, 59(10), 1601–1606. https://doi.org/10.1007/s00262-010-0893-2.

    Article  CAS  PubMed  Google Scholar 

  13. Blees, A., Januliene, D., Hofmann, T., Koller, N., Schmidt, C., Trowitzsch, S., Moeller, A., & Tampé, R. (2017). Structure of the human MHC-I peptide-loading complex. Nature, 551(7681), 525–528. https://doi.org/10.1038/nature24627.

    Article  CAS  PubMed  Google Scholar 

  14. Garrido, C., Algarra, I., Maleno, I., Stefanski, J., Collado, A., Garrido, F., & Garcia-Lora, A. M. (2010). Alterations of HLA class I expression in human melanoma xenografts in immunodeficient mice occur frequently and are associated with higher tumorigenicity. Cancer Immunology, Immunotherapy, 59(1), 13–26. https://doi.org/10.1007/s00262-009-0716-5.

    Article  CAS  PubMed  Google Scholar 

  15. Garrido, F., & Aptsiauri, N. (2019). Cancer immune escape: MHC expression in primary tumours versus metastases. Immunology, 158(4), 255–266. https://doi.org/10.1111/imm.13114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Watson, N. F. S., Ramage, J. M., Madjd, Z., Spendlove, I., Ellis, I. O., Scholefield, J. H., & Durrant, L. G. (2006). Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. International Journal of Cancer, 118(1), 6–10. https://doi.org/10.1002/ijc.21303.

    Article  CAS  PubMed  Google Scholar 

  17. Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011). Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science, 331(6024), 1565–1570. https://doi.org/10.1126/science.1203486.

    Article  CAS  PubMed  Google Scholar 

  18. Garrido, F., Romero, I., Aptsiauri, N., & Garcia-Lora, A. M. (2016). Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype. International Journal of Cancer, 138(2), 271–280. https://doi.org/10.1002/ijc.29375.

    Article  CAS  PubMed  Google Scholar 

  19. Aptsiauri, N., Ruiz-Cabello, F., & Garrido, F. (2018). The transition from HLA-I positive to HLA-I negative primary tumors: The road to escape from T-cell responses. Current Opinion in Immunology, 51, 123–132. https://doi.org/10.1016/j.coi.2018.03.006.

    Article  CAS  PubMed  Google Scholar 

  20. Garrido, C., Romero, I., Berruguilla, E., Cancela, B., Algarra, I., Collado, A., García-Lora, A., & Garrido, F. (2011). Immunotherapy eradicates metastases with reversible defects in MHC class I expression. Cancer Immunology, Immunotherapy, 60(9), 1257–1268. https://doi.org/10.1007/s00262-011-1027-1.

    Article  CAS  PubMed  Google Scholar 

  21. Algarra, I., Collado, A., & Garrido, F. (1997). Altered MHC class I antigens in tumors. International Journal of Clinical & Laboratory Research, 27(2), 95–102. https://doi.org/10.1007/BF02912442.

    Article  CAS  Google Scholar 

  22. Garrido, F. (2019). HLA Class-I Expression and cancer immunotherapy. In MHC Class-I Loss and Cancer Immune Escape (pp. 79–90). Springer International Publishing. https://doi.org/10.1007/978-3-030-17864-2_3.

  23. Natali, P. G., Bigotti, A., Nicotra, M. R., Viora, M., Manfredi, D., & Ferrone, S. (1984). Distribution of human Class I (HLA-A,B,C) histocompatibility antigens in normal and malignant tissues of nonlymphoid origin. Cancer Research, 44(10), 4679–4687.

    CAS  PubMed  Google Scholar 

  24. Garrido, F., Ruiz-Cabello, F., Cabrera, T., Pérez-Villar, J. J., López-Botet, M., Duggan-Keen, M., & Stern, P. L. (1997). Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunology Today, 18(2), 89–95. https://doi.org/10.1016/s0167-5699(96)10075-x.

    Article  CAS  PubMed  Google Scholar 

  25. Marincola, F. M., Jaffee, E. M., Hicklin, D. J., & Ferrone, S. (2000). Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Advances in Immunology, 74, 181–273. https://doi.org/10.1016/s0065-2776(08)60911-6.

    Article  CAS  PubMed  Google Scholar 

  26. Campoli, M., & Ferrone, S. (2008). HLA antigen changes in malignant cells: Epigenetic mechanisms and biologic significance. Oncogene, 27(45), 5869–5885. https://doi.org/10.1038/onc.2008.273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cabrera, T., Angustias Fernandez, M., Sierra, A., Garrido, A., Herruzo, A., Escobedo, A., … Garrido, F. (1996). High frequency of altered HLA class I phenotypes in invasive breast carcinomas. Human Immunology, 50(2), 127–134. https://doi.org/10.1016/0198-8859(96)00145-0

  28. Carretero, F. J., Del Campo, A. B., Flores-Martín, J. F., Mendez, R., García-Lopez, C., Cozar, J. M., et al. (2016). Frequent HLA class I alterations in human prostate cancer: Molecular mechanisms and clinical relevance. Cancer Immunology, Immunotherapy, 65(1), 47–59. https://doi.org/10.1007/s00262-015-1774-5.

    Article  CAS  PubMed  Google Scholar 

  29. del Campo, A. B., Kyte, J. A., Carretero, J., Zinchencko, S., Méndez, R., González-Aseguinolaza, G., Ruiz-Cabello, F., Aamdal, S., Gaudernack, G., Garrido, F., & Aptsiauri, N. (2014). Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. International Journal of Cancer, 134(1), 102–113. https://doi.org/10.1002/ijc.28338.

    Article  CAS  PubMed  Google Scholar 

  30. Cabrera, C. M., Jiménez, P., Cabrera, T., Esparza, C., Ruiz-Cabello, F., & Garrido, F. (2003). Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: Beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Tissue Antigens, 61(3), 211–219. https://doi.org/10.1034/j.1399-0039.2003.00020.x.

    Article  CAS  PubMed  Google Scholar 

  31. Garrido, C., Paco, L., Romero, I., Berruguilla, E., Stefansky, J., Collado, A., Algarra, I., Garrido, F., & Garcia-Lora, A. M. (2012). MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion and intrinsic tumorigenicity of melanoma cells. Carcinogenesis, 33(3), 687–693. https://doi.org/10.1093/carcin/bgr318.

    Article  CAS  PubMed  Google Scholar 

  32. de Kruijf, E. M., Sajet, A., van Nes, J. G. H., Natanov, R., Putter, H., Smit, V. T. H. B. M., Liefers, G. J., van den Elsen, P. J., van de Velde, C. J. H., & Kuppen, P. J. K. (2010). HLA-E and HLA-G Expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients. The Journal of Immunology, 185(12), 7452–7459. https://doi.org/10.4049/jimmunol.1002629.

    Article  CAS  PubMed  Google Scholar 

  33. Esteban, F., Ruiz-Cabello, F., Concha, A., Pérez-Ayala, A., Sánchez-Rozas, J. A., & Garrido, F. (1990). HLA-DR expression is associated with excellent prognosis in squamous cell carcinoma of the larynx. Clinical & Experimental Metastasis, 8(4), 319–328. https://doi.org/10.1007/BF01810678.

    Article  CAS  Google Scholar 

  34. Glew, S. S., Connor, M. E., Snijders, P. J. F., Stanbridge, C. M., Buckley, C. H., Walboomers, J. M. M., Meijer, C. J. L. M., & Stern, P. L. (1993). HLA expression in pre-invasive cervical neoplasia in relation to human papilloma virus infection. European Journal of Cancer, 29(14), 1963–1970. https://doi.org/10.1016/0959-8049(93)90453-M.

    Article  Google Scholar 

  35. Cabrera, T., Garrido, V., Concha, A., Martin, J., Esquivias, J., Oliva, M. R., Ruizcabello, F., Serrano, S., & Garrido, F. (1992). HLA molecules in basal cell carcinoma of the skin. Immunobiology, 185(5), 440–452. https://doi.org/10.1016/S0171-2985(11)80086-0.

    Article  CAS  PubMed  Google Scholar 

  36. Gutierrez, J., Ruiz-Cabello, F., López Nevot, M. A., Cabrera, T., Esquivias, J., & Garrido, F. (1990). Class II HLA antigen expression in familial Polyposis coli is related to the degree of dysplasia. Immunobiology, 180(2), 138–148. https://doi.org/10.1016/S0171-2985(11)80324-4.

    Article  CAS  PubMed  Google Scholar 

  37. Tabibzadeh, S. S., Sivarajah, A., Carpenter, D., Ohlsson-Wilhelm, B. M., & Satyaswaroop, P. G. (1990). Modulation of HLA-DR Expression in epithelial cells by interleukin 1 and estradiol-17β*. The Journal of Clinical Endocrinology & Metabolism, 71(3), 740–747. https://doi.org/10.1210/jcem-71-3-740.

    Article  CAS  Google Scholar 

  38. Oldford, S. A., Robb, J. D., Watson, P. H., & Drover, S. (2004). HLA-DRB alleles are differentially expressed by tumor cells in breast carcinoma. International Journal of Cancer, 112(3), 399–406. https://doi.org/10.1002/ijc.20441.

    Article  CAS  PubMed  Google Scholar 

  39. Ostrand-Rosenberg, S., Baskar, S., Patterson, N., & Sciences, V. K. C. of B. (1996). Expression of MHC Class II and B7–1 and B7–2 costimulatory molecules accompanies tumor rejection and reduces the metastatic potential of tumor cells. Tissue Antigens, 47(5), 414–421. https://doi.org/10.1111/j.1399-0039.1996.tb02577.x.

    Article  CAS  PubMed  Google Scholar 

  40. Kambayashi, T., & Laufer, T. M. (2014). Atypical MHC class II-expressing antigen-presenting cells: Can anything replace a dendritic cell? Nature Reviews. Immunology, 14(11), 719–730. https://doi.org/10.1038/nri3754.

    Article  CAS  PubMed  Google Scholar 

  41. Axelrod, M. L., Cook, R. S., Johnson, D. B., & Balko, J. M. (2019). Biological consequences of MHC-II expression by tumor cells in cancer. Clinical Cancer Research, 25(8), 2392–2402. https://doi.org/10.1158/1078-0432.CCR-18-3200.

    Article  CAS  PubMed  Google Scholar 

  42. Hilton, D. A., & West, K. P. (1990). An evaluation of the prognostic significance of HLA-DR expression in gastric carcinoma. Cancer, 66(6), 1154–1157.

    Article  CAS  Google Scholar 

  43. Brunner, C. A., Gokel, J. M., Riethmüller, G., & Johnson, J. P. (1991). Expression of HLA-D subloci DR and DQ by breast carcinomas is correlated with distinct parameters of favourable prognosis. European Journal of Cancer & Clinical Oncology, 27(4), 411–416. https://doi.org/10.1016/0277-5379(91)90374-M.

    Article  CAS  Google Scholar 

  44. Andersen, S. N., Rognum, T. O., Lund, E., Meling, G. I., & Hauge, S. (1993). Strong HLA-DR expression in large bowel carcinomas is associated with good prognosis. British Journal of Cancer, 68(1), 80–85. https://doi.org/10.1038/bjc.1993.290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. López-Nevot, M. A., Garcia, E., Romero, C., Oliva, M. R., Serrano, S., & Garrido, F. (1988). Phenotypic and genetic analysis of HLA class I and HLA-DR antigen expression on human melanomas. Experimental and Clinical Immunogenetics, 5(4), 203–212.

    PubMed  Google Scholar 

  46. Ting, J. P.-Y., & Trowsdale, J. (2002). Genetic control of MHC class II expression. Cell, 109(Suppl), S21–S33. https://doi.org/10.1016/s0092-8674(02)00696-7.

    Article  CAS  PubMed  Google Scholar 

  47. Garrido, F., Festenstein, H., & Schirrmacher, V. (1976). Further evidence for depression of H-2 and Ia-like specificities of foreign haplotypes in mouse tumour cell lines. Nature, 261(5562), 705–707. https://doi.org/10.1038/261705a0.

    Article  CAS  PubMed  Google Scholar 

  48. Garrido, F., Perez, M., & Torres, M. D. (1979). Absence of four H-2d antigenic specificites in an H-2d sarcoma. Journal of Immunogenetics, 6(2), 83–86. https://doi.org/10.1111/j.1744-313x.1979.tb00333.x.

    Article  CAS  PubMed  Google Scholar 

  49. Algarra, I., Gaforio, J. J., Garrido, A., Mialdea, M. J., Pérez, M., & Garrido, F. (1991). Heterogeneity of MHC-class-I antigens in clones of methylcholanthrene-induced tumors. Implications for local growth and metastasis. International Journal of Cancer. Supplement, 6, 73–81. https://doi.org/10.1002/ijc.2910470716.

    Article  CAS  Google Scholar 

  50. Ballinari, D., Pierotti, M. A., Sensi, M. L., & Parmiani, G. (1983). Lack of H-2Ld locus products on a BALB/c fibrosarcoma expressing H-2k-like alien antigens. Journal of Immunogenetics, 10(2), 115–125. https://doi.org/10.1111/j.1744-313x.1983.tb01024.x.

    Article  CAS  PubMed  Google Scholar 

  51. Rosloniec, E. F., Kuhn, M. H., Genyea, C. A., Reed, A. H., Jennings, J. J., Giraldo, A. A., et al. (1984). Aggressiveness of SJL/J lymphomas correlates with absence of H-2Ds antigens. Journal of Immunology, 132(2), 945–952.

    CAS  Google Scholar 

  52. Green, W. R., Rich, R. F., & Beadling, C. (1988). Differential induction of H-2K versus H-2D class I major histocompatibility antigens by recombinant gamma interferon. Lack of Kk augmentation in a leukemia virus-induced tumor is due to a cis-dominant effect. The Journal of Experimental Medicine, 167(5), 1616–1624. https://doi.org/10.1084/jem.167.5.1616.

    Article  CAS  PubMed  Google Scholar 

  53. Wallich, R., Bulbuc, N., Hämmerling, G. J., Katzav, S., Segal, S., & Feldman, M. (1985). Abrogation of metastatic properties of tumour cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature, 315(6017), 301–305. https://doi.org/10.1038/315301a0.

    Article  CAS  PubMed  Google Scholar 

  54. Ljunggren, H. G., & Kärre, K. (1985). Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. The Journal of Experimental Medicine, 162(6), 1745–1759. https://doi.org/10.1084/jem.162.6.1745.

    Article  CAS  PubMed  Google Scholar 

  55. Seliger, B., Wollscheid, U., Momburg, F., Blankenstein, T., & Huber, C. (2000). Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. Tissue Antigens, 56(4), 327–336. https://doi.org/10.1034/j.1399-0039.2000.560404.x.

    Article  CAS  PubMed  Google Scholar 

  56. Seliger, B., Wollscheid, U., Momburg, F., Blankenstein, T., & Huber, C. (2001). Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. Cancer Research, 61(3), 1095–1099.

    CAS  PubMed  Google Scholar 

  57. Romero, I., Algarra, I., & Garcia-Lora, A. M. (2020). MHC Class I molecules and cancer progression: Lessons learned from preclinical mouse models BT - Cancer immunology: A translational medicine context. In Rezaei, N. (Ed.), (pp. 189–204). Springer International Publishing. https://doi.org/10.1007/978-3-030-30845-2_12

  58. Chen, L., & Flies, D. (2013). Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology, 13(4), 227–242. https://doi.org/10.1038/nri3405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jäger, E., Ringhoffer, M., Karbach, J., Arand, M., Oesch, F., & Knuth, A. (1996). Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T-cell responses: Evidence for immunoselection of antigen-loss variants in vivo. International Journal of Cancer, 66(4), 470–476.

    Article  Google Scholar 

  60. Terabe, M., & Berzofsky, J. A. (2004). Immunoregulatory T cells in tumor immunity. Current Opinion in Immunology, 16(2), 157–162. https://doi.org/10.1016/j.coi.2004.01.010.

    Article  CAS  PubMed  Google Scholar 

  61. Rodríguez, T., Méndez, R., Del Campo, A., Jiménez, P., Aptsiauri, N., Garrido, F., & Ruiz-Cabello, F. (2007). Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines. BMC Cancer, 7, 34. https://doi.org/10.1186/1471-2407-7-34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pfeffer, C. M., & Singh, A. T. K. (2018). Apoptosis: A target for anticancer therapy. International Journal of Molecular Sciences, 19(2), 448. https://doi.org/10.3390/ijms19020448.

    Article  CAS  PubMed Central  Google Scholar 

  63. Gajewski, T., Schreiber, H., & Fu, Y.-X. (2013). Innate and adaptive immune cells in the tumor microenvironment. Nature Immunology, 14(10), 1014–1022. https://doi.org/10.1038/ni.2703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., Gallagher, W. M., Wadhwani, N., Keil, S. D., Junaid, S. A., Rugo, H. S., Hwang, E. S., Jirström, K., West, B. L., & Coussens, L. M. (2011). Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discovery, 1(1), 54–67. https://doi.org/10.1158/2159-8274.CD-10-0028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Akalay, I., Janji, B., Hasmim, M., Noman, M. Z., André, F., De Cremoux, P., … Chouaib, S. (2013). Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell–mediated lysis. Cancer Research, 73(8), 2418–2427. https://doi.org/10.1158/0008-5472.CAN-12-2432

  66. Hamilton, D. H., Huang, B., Fernando, R. I., Tsang, K.-Y., & Palena, C. (2014). WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition. Cancer Research, 74(9), 2510–2519. https://doi.org/10.1158/0008-5472.CAN-13-1894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Beatty, G. L., & Gladney, W. L. (2015). Immune escape mechanisms as a guide for cancer immunotherapy. Clinical Cancer Research, 21(4), 687–692. https://doi.org/10.1158/1078-0432.CCR-14-1860.

    Article  CAS  PubMed  Google Scholar 

  68. Iorgulescu, J. B., Braun, D., Oliveira, G., Keskin, D. B., & Wu, C. J. (2018). Acquired mechanisms of immune escape in cancer following immunotherapy. Genome Medicine, 10(1), 87. https://doi.org/10.1186/s13073-018-0598-2.

    Article  CAS  PubMed  Google Scholar 

  69. Kang, J. K., Yoon, S. J., Kim, N. K., & Heo, D. S. (2000). The expression of MHC class I, TAP1/2, and LMP2/7 gene in human gastric cancer cell lines. International Journal of Oncology, 16(6), 1159–1163. https://doi.org/10.3892/ijo.16.6.1159.

    Article  CAS  PubMed  Google Scholar 

  70. Hudson, A. W., & Ploegh, H. L. (2002). The cell biology of antigen presentation. Experimental Cell Research, 272(1), 1–7. https://doi.org/10.1006/excr.2001.5402.

    Article  CAS  PubMed  Google Scholar 

  71. Meissner, M., Reichert, T. E., Kunkel, M., Gooding, W., Whiteside, T. L., Ferrone, S., & Seliger, B. (2005). Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: Association with clinical outcome. Clinical Cancer Research, 11(7), 2552–2560. https://doi.org/10.1158/1078-0432.CCR-04-2146.

    Article  CAS  PubMed  Google Scholar 

  72. Kloor, M., Becker, C., Benner, A., Woerner, S. M., Gebert, J., Ferrone, S., & von Knebel Doeberitz, M. (2005). Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Research, 65(14), 6418–6424. https://doi.org/10.1158/0008-5472.CAN-05-0044.

    Article  CAS  PubMed  Google Scholar 

  73. Romero, J. M., Jiménez, P., Cabrera, T., Cózar, J. M., Pedrinaci, S., Tallada, M., Garrido, F., & Ruiz-Cabello, F. (2005). Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. International Journal of Cancer, 113(4), 605–610. https://doi.org/10.1002/ijc.20499.

    Article  CAS  PubMed  Google Scholar 

  74. Garrido, F., Cabrera, T., & Aptsiauri, N. (2010). “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: Implications for immunotherapy. International Journal of Cancer, 127(2), 249–256. https://doi.org/10.1002/ijc.25270.

    Article  CAS  PubMed  Google Scholar 

  75. Bubeník, J. (2004). MHC class I down-regulation: Tumour escape from immune surveillance? (review). International Journal of Oncology, 25(2), 487–491.

    PubMed  Google Scholar 

  76. Méndez, R., Rodríguez, T., Del Campo, A., Monge, E., Maleno, I., Aptsiauri, N., … Garrido, F. (2008). Characterization of HLA class I altered phenotypes in a panel of human melanoma cell lines. Cancer Immunology, Immunotherapy, 57(5), 719–729. https://doi.org/10.1007/s00262-007-0411-3

  77. Marincola, F. M., Shamamian, P., Simonis, T. B., Abati, A., Hackett, J., O’Dea, T., … Al, E. (1994). Locus-specific analysis of human leukocyte antigen class I expression in melanoma cell lines. Journal of Immunotherapy with Emphasis on Tumor Immunology, 16(1), 13–23. https://doi.org/10.1097/00002371-199407000-00002

  78. Romero, I., Martinez, M., Garrido, C., Collado, A., Algarra, I., Garrido, F., & Garcia-Lora, A. M. (2012). The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells. The Journal of Pathology, 227(3), 367–379. https://doi.org/10.1002/path.4029.

    Article  CAS  PubMed  Google Scholar 

  79. Pulido, M., Chamorro, V., Romero, I., Algarra, I., S-Montalvo, A., Collado, A., Garrido, F., & Garcia-Lora, A. M. (2020). Restoration of MHC-I on tumor cells by Fhit transfection promotes immune rejection and acts as an individualized immunotherapeutic vaccine. Cancers, 12(6), 1563. https://doi.org/10.3390/cancers12061563.

    Article  CAS  PubMed Central  Google Scholar 

  80. Tseng, J. E., Kemp, B. L., Khuri, F. R., Kurie, J. M., Lee, J. S., Zhou, X., Liu, D., Hong, W. K., & Mao, L. (1999). Loss of Fhit is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers. Cancer Research, 59(19), 4798–4803.

    CAS  PubMed  Google Scholar 

  81. Campiglio, M., Pekarsky, Y., Menard, S., Tagliabue, E., Pilotti, S., & Croce, C. M. (1999). FHIT loss of function in human primary breast cancer correlates with advanced stage of the disease. Cancer Research, 59(16), 3866–3869.

    CAS  PubMed  Google Scholar 

  82. Fouts, R. L., Sandusky, G. E., Zhang, S., Eckert, G. J., Koch, M. O., Ulbright, T. M., Eble, J. N., & Cheng, L. (2003). Down-regulation of fragile histidine triad expression in prostate carcinoma. Cancer, 97(6), 1447–1452. https://doi.org/10.1002/cncr.11201.

    Article  CAS  PubMed  Google Scholar 

  83. Verri, C., Roz, L., Conte, D., Liloglou, T., Livio, A., Vesin, A., … Sozzi, G. (2009). Fragile histidine triad gene inactivation in lung cancer: The European Early Lung Cancer project. American Journal of Respiratory and Critical Care Medicine, 179(5), 396–401. https://doi.org/10.1164/rccm.200807-1153OC

  84. Serrano, A., Tanzarella, S., Lionello, I., Mendez, R., Traversari, C., Ruiz-Cabello, F., & Garrido, F. (2001). Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2’-deoxycytidine treatment. International Journal of Cancer, 94(2), 243–251. https://doi.org/10.1002/ijc.1452.

    Article  CAS  PubMed  Google Scholar 

  85. Fonsatti, E., Nicolay, H. J. M., Sigalotti, L., Calabrò, L., Pezzani, L., Colizzi, F., Altomonte, M., Guidoboni, M., Marincola, F. M., & Maio, M. (2007). Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2’-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clinical Cancer Research, 13(11), 3333–3338. https://doi.org/10.1158/1078-0432.CCR-06-3091.

    Article  CAS  PubMed  Google Scholar 

  86. Maleno, I., López-Nevot, M. A., Cabrera, T., Salinero, J., & Garrido, F. (2002). Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: High frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunology, Immunotherapy, 51(7), 389–396. https://doi.org/10.1007/s00262-002-0296-0.

    Article  CAS  PubMed  Google Scholar 

  87. Garrido, M. A., Rodriguez, T., Zinchenko, S., Maleno, I., Ruiz-Cabello, F., Concha, Á., Olea, N., Garrido, F., & Aptsiauri, N. (2018). HLA class I alterations in breast carcinoma are associated with a high frequency of the loss of heterozygosity at chromosomes 6 and 15. Immunogenetics, 70(10), 647–659. https://doi.org/10.1007/s00251-018-1074-2.

    Article  CAS  PubMed  Google Scholar 

  88. Benitez, R., Godelaine, D., Lopez-Nevot, M. A., Brasseur, F., Jiménez, P., Marchand, M., … Garrido, F. (1998). Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. Tissue Antigens, 52(6), 520–529. https://doi.org/10.1111/j.1399-0039.1998.tb03082.x

  89. Bernal, M., Ruiz-Cabello, F., Concha, A., Paschen, A., & Garrido, F. (2012). Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes. Cancer Immunology, Immunotherapy, 61(9), 1359–1371. https://doi.org/10.1007/s00262-012-1321-6.

    Article  CAS  PubMed  Google Scholar 

  90. Browning, M., Petronzelli, F., Bicknell, D., Krausa, P., Rowan, A., Tonks, S., Murray, N., Bodmer, J., & Bodmer, W. (1996). Mechanisms of loss of HLA class I expression on colorectal tumor cells. Tissue Antigens, 47(5), 364–371. https://doi.org/10.1111/j.1399-0039.1996.tb02571.x.

    Article  CAS  PubMed  Google Scholar 

  91. Wang, Z., Marincola, F. M., Rivoltini, L., Parmiani, G., & Ferrone, S. (1999). Selective histocompatibility leukocyte antigen (HLA)-A2 loss caused by aberrant pre-mRNA splicing in 624MEL28 melanoma cells. The Journal of Experimental Medicine, 190(2), 205–215. https://doi.org/10.1084/jem.190.2.205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Serrano, A., Brady, C. S., Jimenez, P., Duggan-Keen, M. F., Mendez, R., Stern, P., Garrido, F., & Ruiz-Cabello, F. (2000). A mutation determining the loss of HLA-A2 antigen expression in a cervical carcinoma reveals novel splicing of human MHC class I classical transcripts in both tumoral and normal cells. Immunogenetics, 51(12), 1047–1052. https://doi.org/10.1007/s002510000239.

    Article  CAS  PubMed  Google Scholar 

  93. Respa, A., Bukur, J., Ferrone, S., Pawelec, G., Zhao, Y., Wang, E., Marincola, F. M., & Seliger, B. (2011). Association of IFN-γ signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines. Clinical Cancer Research, 17(9), 2668–2678. https://doi.org/10.1158/1078-0432.CCR-10-2114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Abril, E., Real, L. M., Serrano, A., Jimenez, P., García, A., Canton, J., Trigo, I., Garrido, F., & Ruiz-Cabello, F. (1998). Unresponsiveness to interferon associated with STAT1 protein deficiency in a gastric adenocarcinoma cell line. Cancer Immunology, Immunotherapy, 47(2), 113–120. https://doi.org/10.1007/s002620050511.

    Article  CAS  PubMed  Google Scholar 

  95. Dovhey, S. E., Ghosh, N. S., & Wright, K. L. (2000). Loss of interferon-gamma inducibility of TAP1 and LMP2 in a renal cell carcinoma cell line. Cancer Research, 60(20), 5789–5796.

    CAS  PubMed  Google Scholar 

  96. Sucker, A., Zhao, F., Pieper, N., Heeke, C., Maltaner, R., Stadtler, N., Real, B., Bielefeld, N., Howe, S., Weide, B., Gutzmer, R., Utikal, J., Loquai, C., Gogas, H., Klein-Hitpass, L., Zeschnigk, M., Westendorf, A. M., Trilling, M., Horn, S., Schilling, B., Schadendorf, D., Griewank, K. G., & Paschen, A. (2017). Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nature Communications, 8, 15440. https://doi.org/10.1038/ncomms15440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dunn, G. P., Sheehan, K. C. F., Old, L. J., & Schreiber, R. D. (2005). IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Research, 65(8), 3447–3453. https://doi.org/10.1158/0008-5472.CAN-04-4316.

    Article  CAS  PubMed  Google Scholar 

  98. Mittal, D., Gubin, M. M., Schreiber, R. D., & Smyth, M. J. (2014). New insights into cancer immunoediting and its three component phases—Elimination, equilibrium and escape. Current Opinion in Immunology, 27, 16–25. https://doi.org/10.1016/j.coi.2014.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Takeda, K., Nakayama, M., Hayakawa, Y., Kojima, Y., Ikeda, H., Imai, N., Ogasawara, K., Okumura, K., Thomas, D. M., & Smyth, M. J. (2017). IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting. Nature Communications, 8(1), 14607. https://doi.org/10.1038/ncomms14607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Carretero, R., Wang, E., Rodriguez, A. I., Reinboth, J., Ascierto, M. L., Engle, A. M., Liu, H., Camacho, F. M., Marincola, F. M., Garrido, F., & Cabrera, T. (2012). Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes. International Journal of Cancer, 131(2), 387–395. https://doi.org/10.1002/ijc.26471.

    Article  CAS  PubMed  Google Scholar 

  101. Flores-Martín, J. F., Perea, F., Exposito-Ruiz, M., Carretero, F. J., Rodriguez, T., Villamediana, M., Ruiz-Cabello, F., Garrido, F., Cózar-Olmo, J. M., & Aptsiauri, N. (2019). A combination of positive tumor HLA-I and negative PD-L1 expression provides an immune rejection mechanism in bladder cancer. Annals of Surgical Oncology, 26(8), 2631–2639. https://doi.org/10.1245/s10434-019-07371-2.

    Article  PubMed  Google Scholar 

  102. Chen, P.-L., Roh, W., Reuben, A., Cooper, Z. A., Spencer, C. N., Prieto, P. A., Miller, J. P., Bassett, R. L., Gopalakrishnan, V., Wani, K., de Macedo, M. P., Austin-Breneman, J. L., Jiang, H., Chang, Q., Reddy, S. M., Chen, W. S., Tetzlaff, M. T., Broaddus, R. J., Davies, M. A., Gershenwald, J. E., Haydu, L., Lazar, A. J., Patel, S. P., Hwu, P., Hwu, W. J., Diab, A., Glitza, I. C., Woodman, S. E., Vence, L. M., Wistuba, I. I., Amaria, R. N., Kwong, L. N., Prieto, V., Davis, R. E., Ma, W., Overwijk, W. W., Sharpe, A. H., Hu, J., Futreal, P. A., Blando, J., Sharma, P., Allison, J. P., Chin, L., & Wargo, J. A. (2016). Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discovery, 6(8), 827–837. https://doi.org/10.1158/2159-8290.CD-15-1545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Şenbabaoğlu, Y., Gejman, R. S., Winer, A. G., Liu, M., Van Allen, E. M., de Velasco, G., … Hakimi, A. A. (2016). Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biology, 17(1), 231. https://doi.org/10.1186/s13059-016-1092-z

  104. McGranahan, N., Furness, A. J. S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., Jamal-Hanjani, M., Wilson, G. A., Birkbak, N. J., Hiley, C. T., Watkins, T. B. K., Shafi, S., Murugaesu, N., Mitter, R., Akarca, A. U., Linares, J., Marafioti, T., Henry, J. Y., van Allen, E. M., Miao, D., Schilling, B., Schadendorf, D., Garraway, L. A., Makarov, V., Rizvi, N. A., Snyder, A., Hellmann, M. D., Merghoub, T., Wolchok, J. D., Shukla, S. A., Wu, C. J., Peggs, K. S., Chan, T. A., Hadrup, S. R., Quezada, S. A., & Swanton, C. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science, 351(6280), 1463–1469. https://doi.org/10.1126/science.aaf1490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fares, C. M., Van Allen, E. M., Drake, C. G., Allison, J. P., & Hu-Lieskovan, S. (2019). Mechanisms of resistance to immune checkpoint blockade: Why does checkpoint inhibitor immunotherapy not work for all patients? American Society of Clinical Oncology Educational Book, 39, 147–164. https://doi.org/10.1200/EDBK_240837.

    Article  PubMed  Google Scholar 

  106. Milo, I., Bedora-Faure, M., Garcia, Z., Thibaut, R., Périé, L., Shakhar, G., … Bousso, P. (2018). The immune system profoundly restricts intratumor genetic heterogeneity. Science Immunology, 3(29), eaat1435. https://doi.org/10.1126/sciimmunol.aat1435

  107. Romero, I., Garrido, C., Algarra, I., Chamorro, V., Collado, A., Garrido, F., & Garcia-Lora, A. M. (2018). MHC intratumoral heterogeneity may predict cancer progression and response to immunotherapy. Frontiers in Immunology, 9(JAN), 102. https://doi.org/10.3389/fimmu.2018.00102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Garrido, A., Pérez, M., Delgado, C., Garrido, M. L., Rojano, J., Algarra, I., & Garrido, F. (1986). Influence of class I H-2 gene expression on local tumor growth. Description of a model obtained from clones derived from a solid BALB/c tumor. Experimental and Clinical Immunogenetics, 3(2), 98–110.

    CAS  PubMed  Google Scholar 

  109. Pérez, M., Algarra, I., Ljunggren, H. G., Caballero, A., Mialdea, M. J., Gaforio, J. J., Klein, G., Kärre, K., & Garrido, F. (1990). A weakly tumorigenic phenotype with high MHC class-I expression is associated with high metastatic potential after surgical removal of the primary murine fibrosarcoma. International Journal of Cancer, 46(2), 258–261. https://doi.org/10.1002/ijc.2910460219.

    Article  PubMed  Google Scholar 

  110. Garcia-Lora, A., Martinez, M., Algarra, I., Gaforio, J. J., & Garrido, F. (2003). MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components. International Journal of Cancer, 106(4), 521–527. https://doi.org/10.1002/ijc.11241.

    Article  CAS  PubMed  Google Scholar 

  111. Garcia-Lora, A., Algarra, I., Gaforio, J. J., Ruiz-Cabello, F., & Garrido, F. (2001). Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants. International Journal of Cancer, 91(1), 109–119.

    Article  CAS  Google Scholar 

  112. Swanton, C. (2012). Intratumor heterogeneity: Evolution through space and time. Cancer Research, 72(19), 4875–4882. https://doi.org/10.1158/0008-5472.CAN-12-2217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gonzalez, H., Hagerling, C., & Werb, Z. (2018). Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes and Development, 32(19–20), 1267–1284. https://doi.org/10.1101/GAD.314617.118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shembrey, C., Huntington, N. D., & Hollande, F. (2019). Impact of tumor and immunological heterogeneity on the anti-cancer immune response. Cancers, 11(9), 1217. https://doi.org/10.3390/cancers11091217.

    Article  CAS  PubMed Central  Google Scholar 

  115. Romero, I., Garrido, C., Algarra, I., Collado, A., Garrido, F., & Garcia-Lora, A. M. (2014). T lymphocytes restrain spontaneous metastases in permanent dormancy. Cancer Research, 74(7), 1958–1968. https://doi.org/10.1158/0008-5472.CAN-13-2084.

    Article  CAS  PubMed  Google Scholar 

  116. Ikeda, H., Lethé, B., Lehmann, F., van Baren, N., Baurain, J. F., de Smet, C., Chambost, H., Vitale, M., Moretta, A., Boon, T., & Coulie, P. G. (1997). Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity, 6(2), 199–208. https://doi.org/10.1016/s1074-7613(00)80426-4.

    Article  CAS  PubMed  Google Scholar 

  117. Real, L. M., Jimenez, P., Cantón, J., Kirkin, A., García, A., Abril, E., et al. (1998). In vivo and in vitro generation of a new altered HLA phenotype in melanoma-tumour-cell variants expressing a single HLA-class-I allele. International Journal of Cancer, 75(2), 317–323.

    Article  CAS  Google Scholar 

  118. Real, L. M., Jimenez, P., Kirkin, A., Serrano, A., García, A., Cantón, J., Zeuthen, J., Garrido, F., & Ruiz-Cabello, F. (2001). Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient. Cancer Immunology, Immunotherapy, 49(11), 621–628. https://doi.org/10.1007/s002620000154.

    Article  CAS  PubMed  Google Scholar 

  119. Carretero, R., Romero, J. M., Ruiz-Cabello, F., Maleno, I., Rodriguez, F., Camacho, F. M., Real, L. M., Garrido, F., & Cabrera, T. (2008). Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy. Immunogenetics, 60(8), 439–447. https://doi.org/10.1007/s00251-008-0303-5.

    Article  CAS  PubMed  Google Scholar 

  120. Mendez, R., Serrano, A., Jäger, E., Maleno, I., Ruiz-Cabello, F., Knuth, A., & Garrido, F. (2001). Analysis of HLA class I expression in different metastases from two melanoma patients undergoing peptide immunotherapy. Tissue Antigens, 57(6), 508–519. https://doi.org/10.1034/j.1399-0039.2001.057006508.x.

    Article  CAS  PubMed  Google Scholar 

  121. Kloor, M., Michel, S., & von Knebel Doeberitz, M. (2010). Immune evasion of microsatellite unstable colorectal cancers. International Journal of Cancer, 127(5), 1001–1010. https://doi.org/10.1002/ijc.25283.

    Article  CAS  PubMed  Google Scholar 

  122. Failing, J. J., Aubry, M. C., & Mansfield, A. S. (2020). Human leukocyte antigen expression in paired primary lung tumors and brain metastases in non-small cell lung cancer. Cancer Immunology, Immunotherapy, 70, 215–219. https://doi.org/10.1007/s00262-020-02677-7.

    Article  CAS  PubMed  Google Scholar 

  123. McGranahan, N., Rosenthal, R., Hiley, C. T., Rowan, A. J., Watkins, T. B. K., Wilson, G. A., … Swanton, C. (2017). Allele-specific HLA loss and immune escape in lung cancer evolution. Cell, 171(6), 1259-1271.e11. https://doi.org/10.1016/j.cell.2017.10.001

  124. De Mattos-Arruda, L., Sammut, S.-J., Ross, E. M., Bashford-Rogers, R., Greenstein, E., Markus, H., … Caldas, C. (2019). The genomic and immune landscapes of lethal metastatic breast cancer. Cell Reports, 27(9), 2690-2708.e10. https://doi.org/10.1016/j.celrep.2019.04.098

  125. Garrido, F., Aptsiauri, N., Doorduijn, E. M., Garcia Lora, A. M., & van Hall, T. (2016). The urgent need to recover MHC class I in cancers for effective immunotherapy. Current Opinion in Immunology, 39, 44–51. https://doi.org/10.1016/j.coi.2015.12.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lin, P.-Y., Sun, L., Thibodeaux, S. R., Ludwig, S. M., Vadlamudi, R. K., Hurez, V. J., Bahar, R., Kious, M. J., Livi, C. B., Wall, S. R., Chen, L., Zhang, B., Shin, T., & Curiel, T. J. (2010). B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. Journal of Immunology, 185(5), 2747–2753. https://doi.org/10.4049/jimmunol.1000496.

    Article  CAS  Google Scholar 

  127. Özdemir, B. C., & Dotto, G.-P. (2019). Sex hormones and anticancer immunity. Clinical Cancer Research, 25(15), 4603–4610. https://doi.org/10.1158/1078-0432.CCR-19-0137.

    Article  PubMed  Google Scholar 

  128. Wang, S., Zhang, J., He, Z., Wu, K., & Liu, X.-S. (2019). The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex. International Journal of Cancer, 145(10), 2840–2849. https://doi.org/10.1002/ijc.32327.

    Article  CAS  PubMed  Google Scholar 

  129. Capone, I., Marchetti, P., Ascierto, P. A., Malorni, W., & Gabriele, L. (2018). Sexual dimorphism of immune responses: A new perspective in cancer immunotherapy. Frontiers in Immunology, 9, 552. https://doi.org/10.3389/fimmu.2018.00552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fink, A. L., Engle, K., Ursin, R. L., Tang, W.-Y., & Klein, S. L. (2018). Biological sex affects vaccine efficacy and protection against influenza in mice. Proceedings of the National Academy of Sciences of the United States of America, 115(49), 12477–12482. https://doi.org/10.1073/pnas.1805268115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rodig, S. J., Gusenleitner, D., Jackson, D. G., Gjini, E., Giobbie-Hurder, A., Jin, C., … Hodi, F. S. (2018). MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Science Translational Medicine, 10(450), eaar3342. https://doi.org/10.1126/scitranslmed.aar3342

  132. Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D. Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., Saco, J., Homet Moreno, B., Mezzadra, R., Chmielowski, B., Ruchalski, K., Shintaku, I. P., Sanchez, P. J., Puig-Saus, C., Cherry, G., Seja, E., Kong, X., Pang, J., Berent-Maoz, B., Comin-Anduix, B., Graeber, T. G., Tumeh, P. C., Schumacher, T. N. M., Lo, R. S., & Ribas, A. (2016). Mutations associated with acquired resistance to PD-1 blockade in melanoma. The New England Journal of Medicine, 375(9), 819–829. https://doi.org/10.1056/nejmoa1604958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Perea, F., Sánchez-Palencia, A., Gómez-Morales, M., Bernal, M., Concha, Á., García, M. M., … Aptsiauri, N. (2018). HLA class I loss and PD-L1 expression in lung cancer: Impact on T-cell infiltration and immune escape. Oncotarget, 9(3), 4120–4133. https://doi.org/10.18632/oncotarget.23469

  134. Lee, J. H., Shklovskaya, E., Lim, S. Y., Carlino, M. S., Menzies, A. M., Stewart, A., Pedersen, B., Irvine, M., Alavi, S., Yang, J. Y. H., Strbenac, D., Saw, R. P. M., Thompson, J. F., Wilmott, J. S., Scolyer, R. A., Long, G. V., Kefford, R. F., & Rizos, H. (2020). Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nature Communications, 11(1), 1897. https://doi.org/10.1038/s41467-020-15726-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Paco, L., Garcia-Lora, A. M., Casares, C., Cabrera, C., Algarra, I., Collado, A., Maleno, I., Garrido, F., & Lopez-Nevot, M. A. (2007). Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response. International Journal of Cancer, 121(9), 2023–2030. https://doi.org/10.1002/ijc.22925.

    Article  CAS  PubMed  Google Scholar 

  136. Bentebibel, S.-E., Hurwitz, M. E., Bernatchez, C., Haymaker, C., Hudgens, C. W., Kluger, H. M., Tetzlaff, M. T., Tagliaferri, M. A., Zalevsky, J., Hoch, U., Fanton, C., Aung, S., Hwu, P., Curti, B. D., Tannir, N. M., Sznol, M., & Diab, A. (2019). A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discovery, 9(6), 711–721. https://doi.org/10.1158/2159-8290.CD-18-1495.

    Article  CAS  PubMed  Google Scholar 

  137. Ingegnere, T., Mariotti, F. R., Pelosi, A., Quintarelli, C., De Angelis, B., Tumino, N., … Moretta, L. (2019). Human CAR NK cells: A new non-viral method allowing high efficient transfection and strong tumor cell killing. Frontiers in Immunology, 10, 957. https://doi.org/10.3389/fimmu.2019.00957

  138. Vacca, P., Pietra, G., Tumino, N., Munari, E., Mingari, M. C., & Moretta, L. (2020). Exploiting human NK cells in tumor therapy. Frontiers in Immunology, 10, 3013. https://doi.org/10.3389/fimmu.2019.03013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tumino, N., Martini, S., Munari, E., Scordamaglia, F., Besi, F., Mariotti, F. R., Bogina, G., Mingari, M. C., Vacca, P., & Moretta, L. (2019). Presence of innate lymphoid cells in pleural effusions of primary and metastatic tumors: Functional analysis and expression of PD-1 receptor. International Journal of Cancer, 145(6), 1660–1668. https://doi.org/10.1002/ijc.32262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pesce, S., Greppi, M., Tabellini, G., Rampinelli, F., Parolini, S., Olive, D., … Marcenaro, E. (2017). Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. The Journal of Allergy and Clinical Immunology, 139(1), 335-346.e3. https://doi.org/10.1016/j.jaci.2016.04.025

  141. André, P., Denis, C., Soulas, C., Bourbon-Caillet, C., Lopez, J., Arnoux, T., … Vivier, E. (2018). Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell, 175(7), 1731-1743.e13. https://doi.org/10.1016/j.cell.2018.10.014

  142. Donia, M., Harbst, K., van Buuren, M., Kvistborg, P., Lindberg, M. F., Andersen, R., Idorn, M., Munir Ahmad, S., Ellebæk, E., Mueller, A., Fagone, P., Nicoletti, F., Libra, M., Lauss, M., Hadrup, S. R., Schmidt, H., Andersen, M. H., thor Straten, P., Nilsson, J. A., Schumacher, T. N., Seliger, B., Jönsson, G., & Svane, I. M. (2017). Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling. Cancer Research, 77(17), 4562–4566. https://doi.org/10.1158/0008-5472.CAN-16-3172.

    Article  CAS  PubMed  Google Scholar 

  143. Provencio, M., Nadal, E., Insa, A., García-Campelo, M. R., Casal-Rubio, J., Dómine, M., Majem, M., Rodríguez-Abreu, D., Martínez-Martí, A., de Castro Carpeño, J., Cobo, M., López Vivanco, G., del Barco, E., Bernabé Caro, R., Viñolas, N., Barneto Aranda, I., Viteri, S., Pereira, E., Royuela, A., Casarrubios, M., Salas Antón, C., Parra, E. R., Wistuba, I., Calvo, V., Laza-Briviesca, R., Romero, A., Massuti, B., & Cruz-Bermúdez, A. (2020). Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. The Lancet. Oncology, 21(11), 1413–1422. https://doi.org/10.1016/S1470-2045(20)30453-8.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants cofinanced by FEDER funds (EU) from the Instituto de Salud Carlos III (PI12/02031, PI14/01978, PI15/00528, PI17/00197, PI19/01179, PT13/0010/0039 and PT17/0015/0041), Worldwide Cancer Research project 15-1166, Abbott Diagnostics, Junta de Andalucía (Group CTS-143, CTS-3952, CVI-4740 grants). A.M.G.L. was sup.ported by Contract I3-SNS from Junta de Andalucía and ISCIII

Author information

Authors and Affiliations

  1. Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain

    Ignacio Algarra

  2. Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014, Granada, Spain

    Federico Garrido & Angel M. Garcia-Lora

  3. Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain

    Federico Garrido & Angel M. Garcia-Lora

  4. Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain

    Federico Garrido

  5. Unidad de Biobanco, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Angel M. Garcia-Lora

Authors
  1. Ignacio Algarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federico Garrido
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angel M. Garcia-Lora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angel M. Garcia-Lora.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Algarra, I., Garrido, F. & Garcia-Lora, A.M. MHC heterogeneity and response of metastases to immunotherapy. Cancer Metastasis Rev 40, 501–517 (2021). https://doi.org/10.1007/s10555-021-09964-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-021-09964-4

Keywords

Search

Navigation