Tissue-resident memory T-cell immunosurveillance is associated with cigarette smoking before tumor onset.

  • Major Finding: Tissue-resident memory T-cell immunosurveillance is associated with cigarette smoking before tumor onset.

  • Concept: These tissue-resident memory T cells are present before tumor growth and promote immunotherapy resistance.

  • Impact: The microenvironment in which tumors develop can ultimately affect immunogenicity and therapy response.

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Tissue-resident memory T (TRM) cells play a role in blocking cancer progression, but the impact that chronic inflammation has on these cells as well as their function in cancer evolution have not yet been determined. Using lung adenocarcinoma as a model to determine the effects of TRM cells on the evolution of tumor immunogenicity, Weeden and colleagues performed deep profiling of both healthy lung and lung cancer tissue from patients classified as never-smokers (NS) or ever-smokers (ES) and showed an induction of immunosurveillance activity by TRM cells in healthy lung tissue from ES patients. These TRM cells became increasingly activated during the progression from nonmalignant tissue to early-stage and finally late-stage disease in ES patients, while NS patients demonstrated TRM cell activation only in late-stage cancer. Investigation into the contribution of TRM cells to tumor–immune evolution using murine models of lung cancer revealed that TRM cells induced before tumor onset had no effect on tumor burden but did increase the recruitment and activation of host T cells to the tumor. Moreover, immune evasion was enhanced in the presence of preexisting TRM cells, as evidenced by tumor cell loss of antigen presentation molecules. Consequently, tumors grown in a TRM cell–rich environment were resistant to immune checkpoint blockade therapy. Further evaluation of how tumor–immune evolution is impacted by the differing microenvironments of ES and NS tumors indicated that these early immune escape events are detected only in ES tumors. In summary, this work indicates that TRM cells contribute to cancer–immune equilibrium and that immune escape is related to the environment in which tumors arise, which together suggest that selective pressure by the immune system is a critical determinant of tumor immunogenicity.

Weeden CE, Gayevskiy V, Marceaux C, Batey D, Tan T, Yokote K, et al. Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer. Cancer Cell 2023;41:837–52.e6.

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©2023 American Association for Cancer Research
2023
American Association for Cancer Research