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

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: Cancer immunotherapy; Death receptors; Fas ligand; MDSC; PIVAC 17; TIL apoptosis.

Fig. 1

Death receptors. a CD95/Fas is the most studied death receptor. It is ubiquitously expressed and its binding to membrane-bound FasL triggers receptor trimerization and recruits a protein called Fas-associated death domain (FADD) to the intracytoplasmic death domain (DD) of the receptor. This complex activates caspase 8 and initiates the cascade of effector caspases leading to cell apoptosis. b, c TRAIL R1 and TRAIL R2 are the two members of the TRAIL receptor family that trigger apoptosis. They are trimeric receptors and their binding to both forms of TRAIL will recruit FADD and activate caspase 8, leading to cell apoptosis. These receptors are not only present on monocytes, macrophages, Tregs and MDSC, but also on tumor cells. d TNF receptor 1 is a trimeric receptor present on most cells, and it can bind both membrane-bound and soluble TNF. When activated, it can either induce apoptosis or trigger a pro-survival pathway through NFkB activation. These two antagonist responses are regulated by different proteins, as well as by TNFR2. When triggering apoptosis, TNFR1 activation first requires the recruitment of the TNF receptor-associated death domain (TRADD) protein, which then binds to FADD. e DR3 is a death receptor binding TL1A (TNF-like ligand 1A). As for TNFR1, binding of its ligand can lead to apoptosis via TRADD and FADD but also to NFkB activation [111]. f DR6 is a death receptor whose ligand is unknown. It has been proposed that it induces apoptosis through another pathway that might be mitochondrial [112]. g Three members of the TRAIL receptor family do not trigger apoptosis. DcR1 and DcR2 are decoy receptors expressed mostly by lymphocytes and neutrophils. DcR1 has no death domain and DcR2 presents a truncated death domain. OPG is a soluble receptor, binding only soluble TRAIL. h TNFR2 is present on neurons, immune and endothelial cells, and it has also been described on some tumor cells. TNFR2 activation promotes Treg proliferation and MDSC survival. Many intracellular pathways following activation have been described. Activation of NFkB in Tregs is the most established [113]

Fig. 2

Fas–FasL interactions in the tumor microenvironment. Upper panel displays main Fas–FasL interactions; bottom panel represents other suggested Fas–FasL interactions in the TME. Dotted lines represent cells undergoing apoptosis. a MDSC can express FasL to induce CD8 T-cell apoptosis. b Upon activation, CD8 T cells display FasL at their surface, therefore, triggering apoptosis of neighboring CD8 via Fas binding. This physiological feedback mechanism is called AICD and aims at controlling lymphocyte expansion. c Endothelial cells in the tumor express FasL to prevent CD8 T-cell homing and promote their apoptosis, while favoring Treg homing. d On tumor cells, Fas activation leads through different intracellular pathways to tumor growth and increased invasiveness. e CD8 T cells can exert their cytotoxic activity by presenting FasL at their surface, triggering tumor cell apoptosis. Tumor cells could counterattack f locally by presenting FasL at their surface or g from a distance by secreting exosome-like particles presenting FasL. h Tregs might also trigger CD8 T-cell apoptosis through FasL expression. i Antigen-presenting cells (APC) expressing Fas might undergo apoptosis upon binding of FasL expressed by activated T cells. j Fas activation on naïve CD8 T cells could favor their precocious differentiation into memory T cells rather than effector T cells. k CD8 T cells may trigger MDSC apoptosis via FasL