CD103⁺CD8⁺ T_RM Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17

Accumulation of CD103⁺CD8⁺ resident memory T (T_RM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of T_RM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103⁺CD8⁺ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103⁺CD8⁺ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103⁺CD8⁺ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103⁺CD8⁺ tumor T_RM, but not CD103⁻CD8⁺ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103⁺CD8⁺ T_RM are associated with better outcomes in anti-PD-(L)1-treated patients.