低剂量放疗联合免疫治疗小细胞肺癌中 CXCR6(+)CD8(+) T 细胞的动态演变及抗肿瘤机制

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.

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.

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).

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.