CD8+ T cell differentiation and dysfunction in cancer

Abstract

CD8⁺ T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8⁺ T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy. Here we review CD8⁺ T cell differentiation to dysfunctional states during tumorigenesis. We highlight similarities and differences between T cell dysfunction and other hyporesponsive T cell states and discuss the spatio-temporal factors contributing to T cell state heterogeneity in tumours. An important challenge is predicting which patients will respond to immunotherapeutic interventions and understanding which T cell subsets mediate the clinical response. We explore our current understanding of what determines T cell responsiveness and resistance to immunotherapy and point out the outstanding research questions.

Fig. 1 |. Carcinogenesis and tumour-specific CD8⁺ T cell differentiation: a two-phase differentiation programme.

An initiating oncogenic mutation occurs within a single cell in an otherwise normal tissue. Neoantigen-specific (naive) CD8⁺ T cells do not efficiently infiltrate and survey normal peripheral tissues; thus, during early tumorigenesis, tumour-specific CD8⁺ T cells may remain ignorant of antigen-expressing cancer cells. When tumours progress and sufficient tumour antigen is presented in draining lymph nodes, tumour-specific T cells can be activated in the draining lymph node or within tumour tissue in a largely non-inflammatory, non-stimulatory context, inducing an anergic, early dysfunctional T cell state (phase 1). The tumour continues to progress, inducing an immunosuppressive microenvironment. Persistent tumour antigen and microenvironmental signals drive tumour-specific T cells into a late dysfunctional state (phase 2).

Fig. 2 |. Models of CD8⁺ T cell differentiation and dysfunction in tumours and exhaustion during chronic infections.

a | Linear differentiation model. Naive tumour-specific CD8⁺ T cells encounter tumour antigens, inducing a programme of early dysfunction. Dysfunction is initially plastic but eventually becomes fixed. T cell factor 1 (TCF1) is progressively lost with time and antigen encounter, while TOX expression increases. Early dysfunction and late dysfunction are epigenetically encoded and can be associated with specific surface marker and transcription factor expression. Early dysfunctional T cells can be reprogrammed; late dysfunctional T cells are resistant to therapeutic reprogramming. b | Branched differentiation model. Tumour-specific T cells infiltrate the tumour. Tertiary lymphoid structures or lymphoid-like structures could represent specialized niches within the tumour microenvironment that facilitate the maintenance of tumour-specific progenitor-like/less dysfunctional CD8⁺ T cells which self-renew and give rise to more differentiated dysfunctional T cells (terminally differentiated). c | In chronic infection, pathogen-specific T cells differentiate into early effector T cells, which differentiate into progenitor exhausted T cells that reside within secondary lymphoid organs (for example, white pulp of the spleen) and self-renew, and give rise to terminally exhausted T cells found in peripheral tissue and red pulp.

Fig. 3 |. Two modules of tumour-specific T cell dysfunction programming: loss of effector function and exhaustion phenotype.

Tumour-specific T cells in solid tumours are continuously triggered by tumour antigens. Chronic T cell receptor (TCR) stimulation leads to nuclear factor of activated T cells (NFAT)-mediated expression of TOX. TOX induces a programme and phenotype associated with exhaustion, including the expression of inhibitory receptors (such as PD1, LAG3, 2B4 and CD39) and downregulation of transcription factors (such as T cell factor 1 (TCF1)). TOX-mediated exhaustion programming and expression of inhibitory receptors prevents T cells from overstimulation and allows T cells to persist in tumours in the face of chronic tumour antigen encounter. TOX-independent mechanisms may regulate the loss of cytotoxic effector function, including cytokines and cytotoxic molecules. IFNγ, interferon-γ.

Fig. 4 |. Tumour-specific CD8⁺ T cell subsets and states mediating immunotherapy responses.

a | In the tumour, most tumour-reactive T cells are in a late dysfunctional state that is resistant to immunotherapeutic reprogramming (such as with immune checkpoint blockade or vaccination). b,c | Early dysfunctional T cells which recently entered the tumour and/or progenitor/early dysfunctional tumour-specific T cells residing in tertiary lymphoid structures or intratumoural niches can be functionally rescued and reprogrammed into effector T cells by immunotherapy. d | In the periphery, functional or progenitor-like/early dysfunctional tumour-reactive T cells in secondary lymphoid organs or peripheral blood proliferate and differentiate into cytotoxic effector T cells in the presence of immune checkpoint blockade. Reprogrammed functional T cells infiltrate the tumour and mediate tumour elimination.