Resident memory T cells in antitumor immunity and cancer immunotherapy

Abstract

Abstract Tumor-resident memory T (TRM) cells play an important role in cancer diseases. Accumulating evidence indicates that subpopulations of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) are TRM cells, and are emerging as activated tumor-specific T cells. These TRM are characterized by expression of CD103 integrin and identify tumor-reactive cytotoxic T lymphocytes. Human lung tumor CD103+CD8+ TRM co-express CD49a and CD69, and are associated with a favorable prognosis. They also express a panel of T-cell inhibitory receptors, including PD-1, and are able to kill autologous tumor cells upon blockade of PD-1 with neutralizing antibodies. This CD103+CD8+ TRM subset also emerges as a predictive biomarker of response to PD-1 blockade and expands during anti-PD-1 treatment in responder, but not in non-responder patients. It is now widely admitted that expression of CD103 on activated CD8+ T lymphocytes and persistence of TRM in epithelial tissues requires TGF-β. This cytokine is secreted in the tumor microenvironment in its inactive form bound to latency-associated protein, and is activated by αV integrins on tumor cells and immune cells. Using multiplex immunofluorescence staining on cohorts of anti-PD-(L)1-treated lung cancer patients, we recently showed that decreased expression of tumor αV is associated with improved immunotherapy-related-progression-free survival and correlates with an increased density of CD8+CD103+ TIL. Cancer cell αV activates autocrine TGF-β and participates in inducing CD103 on activated CD8+ T cells. Our more recent studies in mouse tumor models and human cancers demonstrate that different CD8+ TRM subsets participate to response different immune checkpoint inhibitors and therapeutic cancer vaccines. Supported by ARC, INCa, Ligue Supported by ARC, INCa, Ligue