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

被引：0
作者：
Guo Lin [1 ]
Zhuoran Yao [2 ]
Kai Kang [1 ]
Ren Luo [2 ]
Linglu Yi [1 ]
You Lu [2 ]
机构：
[1] Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu
[2] Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu
[3] Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu
来源：
Journal of Translational Medicine | / 23卷 / 1期
基金：
中国博士后科学基金;
关键词：
CD8-positive T-lymphocytes; Immunotherapy; Radiotherapy; Small-cell lung cancer; Tumor-infiltrating;
D O I：
10.1186/s12967-025-06450-1
中图分类号：
学科分类号：
摘要：
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. © The Author(s) 2025.
引用
收藏
相关论文
共 70 条
  • [41] Na F., Pan X., Chen J., Chen X., Wang M., Chi P., You L., Zhang L., Zhong A., Zhao L., Et al., KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming, Nat Cancer, 3, 6, pp. 753-767, (2022)
  • [42] Wolf F.A., Hamey F.K., Plass M., Solana J., Dahlin J.S., Gottgens B., Rajewsky N., Simon L., Theis F.J., PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells, Genom Biol, 20, 1, (2019)
  • [43] Wolf F.A., Angerer P., Theis F.J., SCANPY: large-scale single-cell gene expression data analysis, Genom Biol, 19, 1, (2018)
  • [44] Liu Q., Zhang J., Guo C., Wang M., Wang C., Yan Y., Sun L., Wang D., Zhang L., Yu H., Et al., Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies, Cell, 187, 1, pp. 184-203.e128, (2024)
  • [45] George J., Lim J.S., Jang S.J., Cun Y., Ozretic L., Kong G., Leenders F., Lu X., Fernandez-Cuesta L., Bosco G., Et al., Comprehensive genomic profiles of small cell lung cancer, Nature, 524, 7563, pp. 47-53, (2015)
  • [46] Qiu Y., Liu L., Jiang W., Xu Z., Wang J., Dai S., Guo J., Xu J., NKG2A(+)CD8(+) T cells infiltration determines immunosuppressive contexture and inferior response to immunotherapy in clear cell renal cell carcinoma, J Immunother Cancer, (2024)
  • [47] Peng Q., Qiu X., Zhang Z., Zhang S., Zhang Y., Liang Y., Guo J., Peng H., Chen M., Fu Y.X., Et al., PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade, Nat Commun, 11, 1, (2020)
  • [48] Nesbit E.G., Leal T.A., Kruser T.J., What is the role of radiotherapy for extensive-stage small cell lung cancer in the immunotherapy era?, Transl Lung Cancer Res, 8, pp. S153-s162, (2019)
  • [49] Meijer J.J., Leonetti A., Airo G., Tiseo M., Rolfo C., Giovannetti E., Vahabi M., Small cell lung cancer: novel treatments beyond immunotherapy, Semin Cancer Biol, 86, pp. 376-385, (2022)
  • [50] Li H., Zhao Y., Ma T., Shao H., Wang T., Jin S., Liu Z., Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era, Front Immunol, 14, (2023)
1234567