Tumor-resident memory CD8+ T cells have a pivotal role in cancer immunity and immunotherapy.

Abstract

Abstract CD8+ resident memory T (TRM) cells expressing the CD103 integrin frequently accumulate in human lung tumors and are associated with a favorable prognosis. However, the contribution of this T-cell subset to anti-tumor immunity and to the response to immune checkpoint blockade (ICB) immunotherapy has not been established. Using quantitative multiplex immunofluorescence staining on a cohort of non-small-cell lung cancer (NSCLC) patients treated with PD-1-targeted immunotherapy, we show that an increased density of CD103+CD8+ cells in tumors is associated with greatly improved outcome. CD103+CD8+ cells co-expressed CD49a and CD69, and display a molecular profile characterized by expression of PD-1 and CD39 exhaustion markers, and T-bet, AhR and phosphorylated-STAT-3 transcriptions factors, which confer them a Tc1/Tc17 profile. Moreover, CD103+CD8+ tumor TRM cells, but not CD103−CD8+ (non-TRM) tumor-infiltrating counterparts, demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells, and display oligoclonal expansion of specific TCRβ clonotypes. Human lung tumors are also infiltrated by CD103+CD4+ T cells likely suggesting a role for this resident population in orchestrating the antitumor T-cell response. Moreover, data obtained in pre-clinical mouse tumor models demonstrate that the absence of CD103 on CD8+ T cells impact the antitumor immune responses. These results explain why CD103+CD8+ tumor-reactive TRM cells are associated with better outcome in ICB-treated patients.