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

Abstract

Summary 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.

Legend of the Sentinels: Development of Lung Resident Memory T Cells and Their Roles in Diseases

“…Single-cell analysis even discovered a PD-1+TIM-3+IL-7R- T RM cell subset expresses high levels of inhibitory receptors, but remains the ability to proliferate rapidly in situ and displays enhanced capacity to express key cytotoxic molecules and effector cytokines ( 22 ). Since TIM-3+IL-7R- T RM cells are the major cells expressing PD-1, and CD103+CD8+ T RM cells show positive responses towards anti-PD-1 and anti-PD-L1 monoclonal antibodies, the researchers believe that these cells may be the major subset that reacts in anti-PD-1 therapy ( 22 , 68 , 70 ). In combination with the performance of T RM cells in different stages of lung cancer, it has been speculated that T eff cells were influenced by tumor antigens and cytokines such as TGF-β, up-regulate CD39 and CD103, and converted into CD103+ T RM cells.…”

Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells

“…In non-small cell lung carcinoma, CD103 + CD8 + T cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and the ectonucleotidase CD39 [ 84 ]. Genes involved in T cell exhaustion, including BTLA, LAG-3, and TIGIT, were more strongly expressed in CD8 + T RM cells than in KLRG1 + tumor-infiltrating lymphocyte (TIL) subsets.…”

“…Besides circulating T cells, CD8 + T RM cells also play an important role in the efficacy of PD-1/PD-L1 checkpoint blockade. Upon PD-1 blockade, CD103 + CD8 + T RM cells accumulate in tumors of therapy-responding lung cancer patients, and these cells display enhanced proliferation and cytotoxicity toward cancer cells [ 84 ]. In non-small cell lung carcinoma, tumor-specific CD103 + CD8 + TILs, expressing PD-1 and Tim-3, constitute a highly activated subpopulation and represent a prognostic factor for survival [ 42 ].…”

Isolation of tumor-resident CD8+ T cells from human lung tumors

“…Tumors are heterogeneous in terms of the quantity and quality of immune cell types, so the yield of T RM cells depends on the features of the tumor. For complete details on the use and execution of this protocol, please refer to Corgnac et al. (2020) .…”

“…For complete details on the use and execution of this protocol, please refer to Corgnac et al. (2020) .…”