Dynamic evolution and antitumor mechanisms of CXCR6(+)CD8(+) T cells in small cell lung cancer treated with low-dose radiotherapy and immunotherapy.

BACKGROUND: Patients with small-cell lung cancer (SCLC) have the poor prognosis. Current research suggested that low-dose radiotherapy (LDRT) combined with immunotherapy can enhance the immunogenicity of tumor cells, thereby improving antigen presentation and promoting the intratumoral infiltration of CD8(+) T cells, which significantly extends the survival of patients. However, the change trajectory of T cells, and the mechanisms underlying the promotion of intratumoral infiltration of CD8(+) T cells, and the enhancement of their cytotoxic functions remain to be elucidated. METHODS: To delineate the dynamic changes of T cells, we collected tumors from Kaede tumor-bearing mice that had undergone radioimmunotherapy. Using flow cytometry, we sorted intratumoral-infiltrating immune cells, which were required for single-cell RNA sequencing, at various time points (Kaede Red: derived from tumor-draining lymph node [TDLN]). The results obtained from the sequencing analysis were further validated through experiments, such as flow cytometry, immunofluorescence, and analysis of clinical cohort data. RESULTS: Here, we observed stem-like T cells migrating from the TDLN to the tumor site and differentiating into effector phenotypes within the tumor. Dendritic cells (DCs) are the key cluster that induces the differentiation of stem-like T cell into effector phenotypes. Moreover, SCLC patients with a high infiltration of tumor-specific CXCR6(+)CD8(+) T cells exhibited a supportive TME and longer survival time (P < 0.001). CONCLUSIONS: This study delineates the change trajectory of CD8(+) T cells, identifies the crucial role of DCs in T cell differentiation, and highlights the significance of tumor-specific CXCR6(+)CD8(+) T cells in anti-tumor immunity. Future therapeutic strategies for SCLC could focus on enhancing the infiltration of activated DCs and CXCR6(+)CD8(+) T cells within the tumor microenvironment to improve treatment efficacy.