Tumour antigen-induced T cell exhaustion - the archenemy of immune-hot malignancies

Abstract

Two recent studies addressed the functional properties and clinical significance of tumour antigen-specific effector T cells in human melanomas and lung carcinomas using single-cell strategies. Herein, we discuss their findings, which expand our understanding of T cell alterations in the tumour microenvironment and demonstrate that CD8⁺ T cell exhaustion is mediated by exposure to tumour cell-specific antigens and is associated with a tissue-resident memory phenotype.

Fig. 1 ∣. Functional profile of tumour-infiltrating CD8⁺ T_eff cells in human solid tumours.

Tumours can contain variable levels of bystander effector T (T_eff) cells targeting non-tumour epitopes, which lack features of exhaustion and are not expected to mediate cancer cell elimination. Tumours with a high number of these cells could be considered as‘pseudo-hot’ (left) and are likely to be insensitive to immune-checkpoint inhibitors (ICIs). By contrast, immune-hot tumours preferentially contain tumour antigen-specific T_eff cells (right). Continuous antigen stimulation and regulatory signals in the tumour microenvironment (TME) can favour an exhausted T cell phenotype and acquisition of a tissue-resident memory profile.Their accumulation in the TME is associated with reduced sensitivity to ICIs. Therapeutic interventions aiming to achieve and/or maintain a TME with a predominance of tumour antigen-specific non-exhausted T_eff cells would lead to improved clinical responses to ICIs. TCR,T cell receptor. Created with BioRender.com.