Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis

Abstract

SUMMARY CD8+ T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8+ T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.

Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy

“…This strategy was supported by in vitro findings from others demonstrating that PD-1 signaling during early TCR activation can disrupt T cell function and in vivo studies utilizing LCMV, wherein a dysfunctional phenotype was imprinted on cells during acute effector differentiation in response to antigen. 17,19,20 Studies characterizing the impact of blocking TIM-3 signaling also provided rationale for this strategy. 24,25 In particular, we hypothesized that antibody blockade of PD-1 and TIM-3 would enhance therapy in three ways: first, checkpoint blockade would directly enhance the activation (de-repression) of anti-tumor adoptively transferred PD-1 + TIM-3 + Pmel cells; second, blockade of checkpoint molecules on endogenously activated immune effectors would potentiate their activity directly against tumor; and finally, the immune checkpoint blockade may relieve inhibition of the endogenous anti-viral immune response, which provides a highly immunogenic environment to support the expansion of both Pmel and endogenous anti-tumor T cells.…”

“…This was in spite of the evidence that inhibitory receptor signaling during TCR activation or the acute effector differentiation in response to infection leads to dampening of the immune response. 17,19,20 Our findings are significant because they characterize the kinetics of inhibitory receptor expression following the administration of oncolytic virotherapy and test a strategy to take advantage of this expression as a therapeutic target. Furthermore, they highlight the significant differences between inhibitory receptor expression on immune effectors in response to acute virotherapy administration and the current clinical use of inhibitory receptor blockade at late, chronic time points after the development of T cell exhaustion.…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…Recent work provides a detailed picture of effector T cell exclusion based on a b-catenin signaling mechanism [159] . The TME is a metabolically demanding place, with competition for oxygen and nutrients [160][161][162] . Tumor cells can outlast T cells through the induction of T cell anergy or exhaustion, part of a class of phenomena termed T cell dysfunction .…”

The pros and cons of dying tumour cells in adaptive immune responses

“…Previous studies have shown that dying tumour cells can release tumour antigens, which can serve as damage-associated molecular patterns (DAMPs), into the tumour microenvironment 2,3 . These tumour antigens persistently stimulate adaptive immune cells such as CD8 + and CD4 + T cells and induce the latter to acquire a dys functional state called T cell exhaustion 4 . Unlike tolerance to a self-antigen, T cell exhaustion is a dysfunctional state characterized by reduced cytokine production and compromised cellkilling ability 5 .…”