Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections

Abstract

CD8 T cell differentiation is a tightly regulated process generating effector and memory T cells over the course of acute infections. In cancer and chronic infection, this differentiation program is derailed, and antigen-specific CD8 T cells differentiate to a hyporesponsive state generally referred to as T cell exhaustion. Here, we review recent findings on heterogeneity of tumor-specific T cells and exhausted T cells during chronic infections, discussing distinct differentiation state dynamics, fate choices, and functional states. Delineating the regulatory mechanisms defining distinct T cell states and determining the requirements for therapeutic reprogramming of these states will provide needed insights for the design of effective immunotherapies for the treatment of cancer and chronic infections.

Figure 1. Heterogeneity of exhausted CD8 T cells during chronic viral infections.

Virus-specific exhausted CD8 T cells consist of an exhausted TCF1⁺ PD1^int T cell population with memory/stem cell-like characteristics which gives rise to a terminally differentiated, exhausted TCF1^low/neg PD1^hiT cell population. PD1/PDL checkpoint blockade reinvigorates the TCF1⁺ PD1^int progenitor population but not the terminally differentiated TCF1 ^low/neg T cell population.

Figure 2. Heterogeneity of tumor-infiltrating lymphocyte (TIL) populations.

TIL are heterogeneous and include tumor-reactive and non-tumor reactive T cells. Non-tumor reactive, bystander T cells appear functional and cytotoxic, express high levels of TCF1 and no or low levels of inhibitory receptors (IR). Tumor-induced T cell dysfunction is progressive and various dysfunctional states exist depending on spatiotemporal factors including antigen burden and duration of tumor antigen exposure. Tumor-specific T cells are initially TCF1+ but with time lose TCF1 expression, become TCF1 ^low/neg, and upregulate numerous inhibitory receptors (IR+++). It is currently not known if TCF1+ tumor-specific T cells represent a stable, self-renewing population. We hypothesize that, in human tumors, as seen in autochthonous tumor mouse models, reprogrammable and non-reprogrammable dysfunctional T cells may be present. Tumor-reactive T cells are also found in the periphery (e.g. blood and lymph nodes) and typically do not have the ‘exhausted’ phenotype, and these T cells maybe the population most amenable to immunotherapy.