Chromatin states define tumour-specific T cell dysfunction and reprogramming

Abstract

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.

Epigenetic control of innate and adaptive immune memory

“…Several studies have provided insight on the dynamic nature of epigenetic regulation during CD8 + T cell differentiation in response to infection and tumor progression 22–27 . Given the many parallel characteristics between NK cells and CD8 + T cells 1 , we investigated whether these two cytolytic lymphocytes possess any similar epigenetic attributes during memory formation.…”

Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

“…Instead, resistance to population-level changes depended on the presence of Tregs for OVA:K b -binding populations, but not for H60:K b - or 2W:I-A b -binding ones. For these other specificities, resistance to avidity maturation may be epigenetically imprinted, similar to T cell-intrinsic hyporesponsiveness, which makes cells resistant to secondary encounter of antigen (Philip et al, 2017; Schietinger et al, 2012), or may be constrained by regulatory cells distinct from classical Tregs. Studies of T cells in tumor microenvironments that are deemed dysfunctional and of self-specific T cells (Black et al, 2014; Kuball et al, 2009; Malhotra et al, 2016; Moon et al, 2011; Soong et al, 2014; Souders et al, 2007; Wong et al, 2008; Yu et al, 2015) have also revealed that many of these cells are low avidity at the population level, supporting the idea that tolerance, whether spontaneously acquired in the tumor microenvironment or upon self-antigen encounter or, as we show in this study, therapeutically induced by costimulation blockade therapy, may be simultaneously enforced through multiple mechanisms, one of which being the preservation of low-avidity repertoire for the relevant antigen.…”

Understanding the tumor immune microenvironment (TIME) for effective therapy

“…The plasticity and reversibility of T cell exhaustion is an important and open question in studies of tumor immunology. Reversible and irreversible states of T cell exhaustion have been identified 45 , and the irreversible exhausted cells are unresponsive to ICB-like anti-PD-1/anti-PD-L1 therapy 46 . Preventing or reversing T cell exhaustion for long-term tumor control will be challenging, and perhaps simultaneous targeting of other tolerance pathways, such as the immunosuppressive TIME, or encouraging the priming of new T cell clones, might be required to obtain durable antitumor T cell responses.…”