Liver metastases of colorectal cancer contain different subsets of tissue-resident memory CD8 T cells correlated with a distinct risk of relapse following surgery.

Tissue-resident memory (T _RM ) T cells have emerged as key players in cancer immunosurveillance, and their presence has been linked to a favorable clinical outcome in solid cancer patients. Liver metastases exhibit a highly immunosuppressive tumor microenvironment, however, the role and clinical impact of T _RM cell infiltration in colorectal cancer remain elusive. The expression of several tissue residency and activation biomarkers has been investigated on tumor-infiltrating lymphocytes isolated from 26 patients' colorectal cancer liver metastases (CRC liver metastases) and compared to 16 peripheral blood samples of patients with CRC liver metastases. Cytokine production was also evaluated in in vitro-activated T _RM and non-T _RM cells. The prognostic value of T _RM cells was also assessed in a well-defined cohort of CRC liver metastases. Here we identified two subsets of T _RM cells expressing CD103 and/or CD69 showing significantly higher expression of tissue residency and activation biomarkers. CD103 ⁺ CD69 ⁺ T _RM cells subset showed almost exclusive expression of tumor reactivity biomarkers PD-1 and CD39. Supporting this observation, CD103 ⁺ CD69 ⁺ T _RM cells showed a more oligoclonal TCR repertoire. Both T _RM subsets presented higher cytotoxic and functional capacity compared to non-T _RM cells. Our study shows that only the presence of CD103 ⁺ CD69 ⁺ T _RM cells is associated with longer recurrence-free survival of colorectal cancer patients with liver metastases. Taken together, our work demonstrates the existence of a phenotypic heterogeneity of T _RM cells in colorectal cancer liver metastases. In this study, we identified a population of CD103 ⁺ CD69 ⁺ T _RM cells exhibiting the characteristics of tumor reactivity and correlated with better patients' prognosis, with potential implications in optimal therapeutic strategies determination.