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Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism

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Abstract

Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid-derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of “cold” tumors that fail to respond to immunotherapy. Interfering with the Fas–FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy.

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Abbreviations

ACT:

Adoptive cell transfer

AICD:

Activation-induced cell death

AKT:

Protein kinase B

ALPS:

Autoimmune lymphoproliferative Syndrome

APC:

Antigen-presenting cells

CAF:

Cancer-associated fibroblast

c-FLIP:

Cellular FLICE-inhibitory protein

DD:

Death domain

EMT:

Epithelial-to-mesenchymal transition

FADD:

Fas-associated death domain

FasL:

Fas ligand

GEMM:

Genetically engineered mouse model

HGFR:

Hepatocyte growth factor

IFNγ:

Interferon-gamma

MAGE:

Melanoma-associated antigens

MDM:

Monocyte-derived human macrophage

MMP:

Matrix metalloproteinase

NSCLC:

Non-small cell lung cancer

OPG:

Osteoprotegerin

PD-L2:

Programmed death ligand 2

PMN-MDSC:

Polymorphonuclear myeloid-derived suppressor cell

TAM:

Tumor-associated macrophage

TCRP1A:

Anti-P1A T-cell receptor

TL1A:

TNF-like ligand 1A

TME:

Tumor microenvironment

TRADD:

TNF receptor-associated death domain

Tregs:

Regulatory T lymphocytes

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We are grateful to Ms. Auriane Sibille for her precious help in the preparation of this manuscript.

Funding

Pierre-Florent Petit is supported by a fellowship from the Fonds National de la Recherche Scientifique (FNRS-Aspirant grant No. 1.A.818.18).

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, 1200, Brussels, Belgium

    Jingjing Zhu, Pierre-Florent Petit & Benoit J. Van den Eynde

  2. de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75 B1.74.03, 1200, Brussels, Belgium

    Jingjing Zhu, Pierre-Florent Petit & Benoit J. Van den Eynde

  3. Walloon Excellence in Life Sciences and Biotechnology, 1200, Brussels, Belgium

    Jingjing Zhu & Benoit J. Van den Eynde

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  1. Jingjing Zhu
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  2. Pierre-Florent Petit
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Jingjing Zhu and Benoit J. Van den Eynde conceived the manuscript. Pierre-Florent Petit designed the figures. All authors contributed to writing and revision of the manuscript.

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Correspondence to Benoit J. Van den Eynde.

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Zhu, J., Petit, PF. & Van den Eynde, B.J. Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism. Cancer Immunol Immunother 68, 835–847 (2019). https://doi.org/10.1007/s00262-018-2269-y

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