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Resident memory T cells (T RM ) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103 +  T RM  are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intratumoral CD103 + CD8 +  tumor infiltrating lymphocytes (TILs), with T RM  properties, are a positive prognostic marker. To better understand the role of T RM  in tumors, we performed a detailed characterization of CD8 +  and CD4 +  TIL phenotype and functional properties in non-small cell lung cancer (NSCLC). Frequencies of CD8 +  and CD4 +  T cell infiltrates in tumors were comparable, but we observed a sharp contrast in T RM  ratios compared to surrounding lung tissue. The majority of both CD4 +  and CD8 +  TILs expressed CD69 and a subset also expressed CD103, both hallmarks of T RM . While CD103 + CD8 +  T cells were enriched in tumors, CD103 + CD4 +  T cell frequencies were decreased compared to surrounding lung tissue. Furthermore, CD103 + CD4 +  and CD103 + CD8 +  TILs showed multiple characteristics of T RM , such as elevated expression of CXCR6 and CD49a, and decreased expression of T-bet and Eomes. In line with the immunomodulatory role of the tumor microenvironment, CD8 +  and CD4 +  TILs expressed high levels of inhibitory receptors 2B4, CTLA-4, and PD-1, with the highest levels found on CD103 +  TILs. Strikingly, CD103 + CD4 +  TILs were the most potent producers of TNF-α and IFN-γ, while other TIL subsets lacked such cytokine production. Whereas, CD103 + CD4 + PD-1 low  TILs produced the most effector cytokines, CD103 + CD4 + PD-1 ++  and CD69 + CD4 + PD-1 ++  TILs produced CXCL13. Furthermore, a large proportion of TILs expressed co-stimulatory receptors CD27 and CD28, unlike lung T RM , suggesting a less differentiated phenotype. Agonistic triggering of these receptors improved cytokine production of CD103 + CD4 +  and CD69 + CD8 +  TILs. Our findings thus provide a rationale to target CD103 + CD4 +  TILs and add co-stimulation to current therapies to improve the efficacy of immunotherapies and cancer vaccines.

Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC