CD8+ Tumor-Infiltrating Lymphocytes Are Primed for Fas-Mediated Activation-Induced Cell Death But Are Not Apoptotic In Situ

Abstract

Induction of Fas-mediated activation-induced cell death in antitumor T cells has been hypothesized to permit tumor escape from immune destruction. Several laboratories have proposed that expression of Fas ligand (L) by tumor is the basis for this form of T cell tolerance. In this study, we characterized murine tumor-infiltrating lymphocytes (TIL) for activation status, cell cycle status, level of apoptosis, cytokine secretion, and proliferative capacity. TILs express multiple activation markers (circa CD69, CD95L, CD122, and LFA-1) and contain IL-2 and IFN-γ mRNAs, but are neither cycling nor apoptotic in situ. In addition, TIL are dramatically suppressed in proliferative response and do not secrete IL-2 and IFN-γ. However, upon purification and activation in vitro, TIL secrete high levels of IL-2 and IFN-γ, enter S phase, and then die by Fas-mediated apoptosis. Activation by injection of anti-TCR Ab or IL-2 into tumor-bearing mice induced TIL entrance into S phase preceding apoptosis, showing that TIL have functional TCR-mediated signal transduction in situ. Our data demonstrate that TIL, not tumor, express both Fas and FasL, are arrested in G1, do not secrete cytokine in situ, and, upon activation in vitro and in vivo, rapidly die by activation-induced cell death.

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

“…23 and 24). Some authors have reported increased apoptosis of tumorinfiltrating lymphocytes (25), although contrary findings have also been shown (26). We hypothesized that myeloid cells localized in tumor tissues, and ones localized in peripheral lymphoid organs (spleen) may differ in their ability to suppress T cell responses.…”

Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes

“…Tumor-specific CD8 T cells lacking effector activity have been isolated from progressing tumors (11)(12)(13), as well as tumor-infiltrated LN of melanoma patients (17,18). In most of these reports, the basis for dysfunction was not established, although the ability to detect these cells in significant numbers suggests that they were able to proliferate in response to Ag at some point.…”

“…In some cases, such dysfunctional CD8 T cells have been isolated from tumors (11)(12)(13). If such T cells are rested in vitro, they recover effector function (11,12), suggesting that factors in the tumor microenvironment suppress the effector activity of otherwise fully differentiated T cells. Several tumors or cells infiltrating tumor masses secrete immunosuppressive cytokines such as TGF-␤ and IL- 10 (14, 15), and these factors may induce local suppression of CD8 T cells.…”

FASL polymorphism is associated with response to bacillus Calmette-Guérin immunotherapy in bladder cancer

“…This mechanism involves the overexpression of both Fas and FasL upon activation by antigen or other stimuli, subsequently pro oti g ell suicide or fratricide [3]. Decreased Fas and elevated FasL expression has been found in many types of cancer including bladder cancer [4].…”