Skip to main content

Advertisement

SpringerLink
Log in

The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

On-treatment steroids for countering immune checkpoint inhibitor-induced inflammatory responses (irAEs) are a hallmark of cancer immunotherapy. However, the suppressive nature of steroids has raised questions regarding their ability to compromise the function of the ‘proliferative burst’ of effector T cells induced by immune checkpoint antibodies. We investigated the effector functions and the co-inhibitory receptor profile of stimulated peripheral blood mononuclear cells (PBMCs) pre-treated with prednisone and dexamethasone alone or in the presence of anti-PD-1/CTLA-4 antibodies. Also, clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) in the presence of glucocorticoids was done. We found that prednisone in contrast to dexamethasone did not compromise T cell cytokine production (IL-2, IFN-γ and TNF-α) and proliferation in the absence or presence of anti-PD-1/CTLA-4 antibodies, when a physiological concentration was used. Neither single prednisone treatment nor co-treatment with checkpoint inhibitors impacted the expression of co-inhibitory receptors PD-1, CTLA-4, TIM-3 and LAG-3. In contrast, dexamethasone treatment promoted downregulation of LAG-3 expression by T cells. In addition, co-treatment of PD-1 + Jurkat cells with prednisone and/or dexamethasone with anti-PD-1 before stimulation significantly reduced SHP-2 phosphorylation, indicative of increased T cell function. Our findings hereby demonstrate a differential steroid effect on T cell function, which should be taken into consideration for patients undergoing immunotherapy. Also, the clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) therapy indicated complete metabolic response in the presence of glucocorticoids. Therefore, concomitant use of prednisone does not appear to interfere with the function of immune checkpoint blockade.

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
Fig. 6

Similar content being viewed by others

Abbreviations

CTLA-4 :

Cytotoxic T lymphocyte-associated protein 4

irAEs :

Immune-related adverse events

LAG-3 :

Lymphocyte activation gene 3

NFAT :

Nuclear factor of activated T cells

PBMCs :

Peripheral blood mononuclear cells

PD-1 :

Programmed cell death-1

PD-L1 :

Programmed cell death-ligand 1

SEB :

Staphylococcus enterotoxin B

SHP-2 :

Src homology region 2-domain phosphatase 2

TIGIT :

T cell immunoreceptor with Ig and ITIM domains

TIM-3 :

T-cell immunoglobulin and mucin-domain containing-3

References

  1. Okoye IS, Houghton M, Tyrrell L, Barakat K, Elahi S (2017) Coinhibitory receptor expression and immune checkpoint blockade: Maintaining a balance in CD8+T cell responses to chronic viral infections and cancer. Front Immunol. https://doi.org/10.3389/fimmu.2017.01215

    Article  PubMed  PubMed Central  Google Scholar 

  2. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DAA, Wherry EJ (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37

    Article  CAS  Google Scholar 

  3. Thommen DS, Schreiner J, Muller P et al (2015) Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res 3(12):1344–1355

    Article  CAS  Google Scholar 

  4. Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908–918

    Article  CAS  Google Scholar 

  5. Callahan MK, Flaherty CR, Postow MA (2016) Checkpoint blockade for the treatment of advanced melanoma. Cancer Treat Res 167:231–250

    Article  Google Scholar 

  6. Hakenberg OW (2017) Nivolumab for the treatment of bladder cancer. Expert Opin Biol Ther. https://doi.org/10.1080/14712598.2017.1353076

    Article  PubMed  Google Scholar 

  7. Rini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1816714

    Article  PubMed  PubMed Central  Google Scholar 

  8. Antonia SJ, López-Martin JA, Bendell J et al (2016) Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. https://doi.org/10.1016/S1470-2045(16)30098-5

    Article  PubMed  PubMed Central  Google Scholar 

  9. Economopoulou P, Agelaki S, Perisanidis C, Giotakis EI, Psyrri A (2016) The promise of immunotherapy in head and neck squamous cell carcinoma. Ann Oncol. https://doi.org/10.1093/annonc/mdw226

    Article  PubMed  Google Scholar 

  10. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ (2015) Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. https://doi.org/10.1038/nrc3907

    Article  PubMed  PubMed Central  Google Scholar 

  11. Myint ZW, Goel G (2017) Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress. J Hematol Oncol. https://doi.org/10.1186/s13045-017-0454-7

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15:486–499

    Article  CAS  Google Scholar 

  13. Marrone KA, Ying W, Naidoo J (2016) Immune-related adverse events from immune checkpoint inhibitors. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.394

    Article  PubMed  Google Scholar 

  14. Michot JM, Bigenwald C, Champiat S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148

    Article  CAS  Google Scholar 

  15. Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1503093

    Article  PubMed  PubMed Central  Google Scholar 

  16. El Osta B, Hu F, Sadek R, Chintalapally R, Tang SC (2017) Not all immune-checkpoint inhibitors are created equal: Meta-analysis and systematic review of immune-related adverse events in cancer trials. Crit Rev Oncol Hematol. https://doi.org/10.1016/j.critrevonc.2017.09.002

    Article  PubMed  Google Scholar 

  17. Hofmann L, Forschner A, Loquai C et al (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–209

    Article  CAS  Google Scholar 

  18. Wozniak S, Mackiewicz-Wysocka M, Krokowicz L, Kwinta L, Mackiewicz J (2015) Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab—case report. Oncol Res Treat 38:105–108

    Article  Google Scholar 

  19. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP (2016) Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 28:254–263

    Article  CAS  Google Scholar 

  20. Ahmed T, Pandey R, Shah B, Black J (2015) Resolution of ipilimumab induced severe hepatotoxicity with triple immunosuppressants therapy. BMJ Case Rep. https://doi.org/10.1136/bcr-2014-208102

    Article  PubMed  PubMed Central  Google Scholar 

  21. Horvat TZ, Adel NG, Dang T-O et al (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 33:3193–3198

    Article  CAS  Google Scholar 

  22. Friedman CF, Proverbs-Singh TA, Postow MA (2016) Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2016.1051

    Article  PubMed  Google Scholar 

  23. Harmankaya K, Erasim C, Koelblinger C, Ibrahim R, Hoos A, Pehamberger H, Binder M (2011) Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol. https://doi.org/10.1007/s12032-010-9606-0

    Article  PubMed  Google Scholar 

  24. Pawarode A, D’Souza A, Pasquini MC et al (2017) Phase 2 study of pembrolizumab during lymphodepleted state after autologous hematopoietic cell transplantation in multiple myeloma patients. Blood 130:339

    Google Scholar 

  25. Garant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, Vuong T (2017) Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review. Crit Rev Oncol Hematol. https://doi.org/10.1016/j.critrevonc.2017.10.009

    Article  PubMed  Google Scholar 

  26. Arbour KC, Mezquita L, Long N et al (2018) Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 36:2872–2878

    Article  CAS  Google Scholar 

  27. Martínez Bernal G, Mezquita L, Auclin E et al (2017) Baseline corticosteroids (CS) could be associated with absence of benefit to immune checkpoint inhibitors (ICI) in advanced non-small cell lung cancer (NSCLC) patients. Ann Oncol. https://doi.org/10.1093/annonc/mdx380.025

    Article  Google Scholar 

  28. Della Corte CM, Morgillo F (2019) Early use of steroids affects immune cells and impairs immunotherapy efficacy. ESMO Open. https://doi.org/10.1136/esmoopen-2018-000477

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fucà G, Galli G, Poggi M et al (2019) Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open. https://doi.org/10.1136/esmoopen-2018-000457

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schadendorf D, Wolchok JD, Stephen Hodi F et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. https://doi.org/10.1200/JCO.2017.73.2289

    Article  PubMed  PubMed Central  Google Scholar 

  31. Weber JS, Larkin JMG, Schadendorf D et al (2018) Management of gastrointestinal (GI) toxicity associated with nivolumab (NIVO) plus ipilimumab (IPI) or IPI alone in phase II and III trials in advanced melanoma (MEL). J Clin Oncol. https://doi.org/10.1200/jco.2017.35.15_suppl.9523

    Article  PubMed  PubMed Central  Google Scholar 

  32. Giles AJ, Hutchinson M-KND, Sonnemann HM et al (2018) Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 6:51

    Article  Google Scholar 

  33. Maxwell R, Luksik AS, Garzon-Muvdi T et al (2018) Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology. https://doi.org/10.1080/2162402X.2018.1500108

    Article  PubMed  PubMed Central  Google Scholar 

  34. Okoye I, Namdar A, Xu L, Crux N, Elahi S (2017) Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling. Oncotarget 8:98215–98232

    Article  Google Scholar 

  35. Elahi S, Dinges WL, Lejarcegui N, Laing KJ, Collier AC, Koelle DM, McElrath MJ, Horton H (2011) Protective HIV-specific CD8(+) T cells evade T(reg) cell suppression. Nat Med 17:989–995

    Article  CAS  Google Scholar 

  36. Ganesan A, Ahmed M, Okoye I et al (2019) Comprehensive in vitro characterization of PD-L1 small molecule inhibitors. Sci Rep. https://doi.org/10.1038/s41598-019-48826-6

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945–954

    Article  CAS  Google Scholar 

  38. Hui E, Cheung J, Zhu J et al (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science (80-). https://doi.org/10.1126/science.aaf1292

    Article  PubMed Central  Google Scholar 

  39. Lorenz U (2009) SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev. https://doi.org/10.1111/j.1600-065X.2008.00760.x

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yu DTY, Clements PJ, Paulus HE, Peter JB, Levy J, Barnett EV (1974) Human lymphocyte subpopulations. Effect of corticosteroids. J Clin Investig. https://doi.org/10.1172/JCI107591

    Article  PubMed  Google Scholar 

  41. Libert C, Dejager L (2014) How steroids steer T cells. Cell Rep. https://doi.org/10.1016/j.celrep.2014.04.041

    Article  PubMed  Google Scholar 

  42. Boland EW (1962) Clinical comparison of the newer anti-inflammatory corticosteroids. Ann Rheum Dis. https://doi.org/10.1136/ard.21.2.176

    Article  PubMed  PubMed Central  Google Scholar 

  43. Xing K, Gu B, Zhang P, Wu X (2015) Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: An insight into the optimum application of glucocorticoids in anti-cancer therapy. BMC Immunol. https://doi.org/10.1186/s12865-015-0103-2

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yarchoan M, Johnson BA, Lutz ER, Laheru DA, Jaffee EM (2017) Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. https://doi.org/10.1038/nrc.2016.154

    Article  PubMed  PubMed Central  Google Scholar 

  45. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: Immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. https://doi.org/10.1038/nrclinonc.2016.25

    Article  PubMed  PubMed Central  Google Scholar 

  46. Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, Togashi Y, Sakai C, Wolchok JD, Nishikawa H (2019) Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids. J Exp Med. https://doi.org/10.1084/jem.20190738

    Article  PubMed  PubMed Central  Google Scholar 

  47. Xia M, Gasser J, Feige U (1999) Dexamethasone enhances CTLA-4 expression during T cell activation. Cell Mol Life Sci. https://doi.org/10.1007/s000180050403

    Article  PubMed  Google Scholar 

  48. Salmond RJ, Alexander DR (2006) SHP2 forecast for the immune system: fog gradually clearing. Trends Immunol 27:154–160

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the University of Alberta Faculty of Medicine and Dentistry’s Flow cytometry facility, which has received financial support from the faculty of Medicine and Dentistry and the Canadian Foundation for Innovation (CFI) awards to contributing investigators.

Funding

This work was supported by the Canadian Institutes of Health Research (CIHR), a CIHR New Investigator Salary Award (360929), an a CIHR Foundation Scheme Grant (353953) (all to S.E.). Alberta Cancer Foundation also supported the clinical study (to J.W. and S.E).

Author information

Authors and Affiliations

  1. Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G2E1, Canada

    Isobel S. Okoye, Lai Xu & Shokrollah Elahi

  2. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G2E1, Canada

    John Walker & Shokrollah Elahi

  3. Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G2E1, Canada

    Shokrollah Elahi

  4. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, T6G2E1, Canada

    Shokrollah Elahi

Authors
  1. Isobel S. Okoye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shokrollah Elahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

IO performed SHP-2, luminescence, some of the ELISA assays, processed sample related to the case study, analyzed the data and wrote the manuscript. LX conducted most of the ELISA assays, CFSE, and the effects of prednisone and dexamethasone on co-inhibitory receptors expression. JW performed clinical study on the patient and contributed in conceiving the original idea. SE conceived the original idea, designed and supervised all of the research, assisted in data analysis and wrote the manuscript.

Corresponding author

Correspondence to Shokrollah Elahi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Consent for publication

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

Ethics approval and consent to participate

The appropriate Institutional Review Boards at the University of Alberta approved the studies, IRB #Pro00046064.

Informed consent

All study participants gave written informed consent to participate in this study.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 217 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okoye, I.S., Xu, L., Walker, J. et al. The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade. Cancer Immunol Immunother 69, 1423–1436 (2020). https://doi.org/10.1007/s00262-020-02555-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-020-02555-2

Keywords

Search

Navigation