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

Dynamic evolution and antitumor mechanisms of CXCR6CD8 T cells in small cell lung cancer treated with low-dose radiotherapy and immunotherapy.

作者信息

Lin Guo, Yao Zhuoran, Kang Kai, Luo Ren, Yi Linglu, Lu You

机构信息

Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.

出版信息

J Transl Med. 2025 Apr 17;23(1):453. doi: 10.1186/s12967-025-06450-1.

DOI:10.1186/s12967-025-06450-1

PMID:40247265

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12007177/

Abstract

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 CXCR6CD8 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 CXCR6CD8 T cells in anti-tumor immunity. Future therapeutic strategies for SCLC could focus on enhancing the infiltration of activated DCs and CXCR6CD8 T cells within the tumor microenvironment to improve treatment efficacy.

摘要

背景

小细胞肺癌（SCLC）患者预后较差。目前的研究表明，低剂量放疗（LDRT）联合免疫疗法可增强肿瘤细胞的免疫原性，从而改善抗原呈递并促进CD8 T细胞在肿瘤内浸润，显著延长患者生存期。然而，T细胞的变化轨迹、促进CD8 T细胞肿瘤内浸润及其细胞毒性功能增强的机制仍有待阐明。

方法

为了描绘T细胞的动态变化，我们从接受放射免疫治疗的Kaede荷瘤小鼠中收集肿瘤。使用流式细胞术，我们在不同时间点（Kaede Red：源自肿瘤引流淋巴结[TDLN]）对肿瘤内浸润的免疫细胞进行分选，这些细胞是单细胞RNA测序所必需的。测序分析结果通过流式细胞术、免疫荧光和临床队列数据分析等实验进一步验证。