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Cancer Immunology, Immunotherapy

, Volume 68, Issue 5, pp 835–847 | Cite as

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

  • Jingjing Zhu
  • Pierre-Florent Petit
  • Benoit J. Van den EyndeEmail author
Focussed Research Review

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.

Keywords

Death receptors TIL apoptosis Cancer immunotherapy MDSC Fas ligand PIVAC 17 

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

Notes

Acknowledgements

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

Author contributions

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.

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ludwig Institute for Cancer ResearchBrusselsBelgium
  2. 2.de Duve InstituteUniversité catholique de LouvainBrusselsBelgium
  3. 3.Walloon Excellence in Life Sciences and BiotechnologyBrusselsBelgium

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