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Tumour-reactive T cells infiltrating solid tumours are often rendered exhausted, a cell differentiation state characterised by upregulation of inhibitory receptors and reduced effector function. The process of T-cell exhaustion permits cancer progression and interferes with immunotherapy response. Efforts to overcome T-cell exhaustion, such as immune checkpoint blockade (ICB), can lead to remarkable clinical responses in some patients with cancer. However, only a minority of patients respond to ICB, responses often lack durability, and undesirable immune-related toxicities are prevalent. Thus, elucidating additional factors that limit T-cell function in cancer may reveal new therapeutic targets to safely promote tumour eradication.
While persistent T-cell receptor (TCR) signalling due to chronic tumour antigen is a major driver of exhaustion, the suppressive tumour microenvironment (TME) also contributes.1 Over the last two decades, the ectoenzymes CD39 and CD73, which degrade extracellular ATP to adenosine, have been implicated in T-cell exhaustion.2 3 In cancer, stressed or damaged cells release ATP. Subsequently, CD39 and CD73 work in concert to convert extracellular ATP to adenosine, which has broad immunosuppressive effects.2 3 In T cells, adenosine regulates proximal TCR signalling events, thereby reducing T-cell effector function. CD39 is highly expressed on exhausted T cells found in human cancers4 5 and cancer or persistent viral infection mouse models.6–8
Here, Potenza et al9 investigate the phenotypic traits of human T cells infiltrating colorectal cancer (CRC) tumours and metastases. Using transcriptional profiling, flow cytometry and …
Contributors AKT and IMS cowrote the commentary.
Funding AKT is supported by NIH T32CA009138-48. IMS is supported by NIH R01 CA254849, CA249393, R01 CA255039, U54 CA268069, P01 CA254849, DOD W81XWH2110525, an AACR Pancreatic Cancer Action Network Catalyst Award (19-35-STRO) and American Cancer Society RSG-21-102-01-IBCD.
Competing interests IMS serves on scientific advisory boards for Immunogenesis and Luminary Therapeutics and has patents in TCR engineering approaches, not directly related to this commentary.
Provenance and peer review Commissioned; externally peer reviewed.