IL-21 enhances the cytotoxicity of intratumoral CD8⁺ T cells, improving radiation efficacy

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Abstract

Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger antitumor immunity. IL-21, an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhanced the TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.

Authors

Xin-yang Li, Xue-qi Xie, Bao-chao Wei, Xiao-zheng Sun, Min-xin Chen, Ru-fei Liu, Qing-xu Tao, Yi-heng Huang, Qian Wang, Shuang-shuang Ma, Ling Wei, Rong Xiao, Zhao-yun Liu, Jin-ming Yu, Meng Wu, Dawei Chen