CD103+CD8+ TRM 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-beta clonotypes. These results explain why CD103(+)CD8(+) T-RM are associated with better outcomes in anti-PD-(L)1-treated patients.