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

## TL;DR

IL-21 improves radiotherapy by boosting CD8+ T cell activity in tumors, potentially enhancing cancer treatment outcomes.

## Contribution

This study demonstrates that IL-21 synergizes with radiotherapy to enhance antitumor immunity via CD8+ T cell activation.

## Key findings

- IL-21 combined with radiation increased CD8+ T cell cytotoxicity and reduced tumor burden in mouse models.
- Humanized mice showed enhanced CD8+ T cell function and reduced A549 tumor growth with IL-21 and radiation.
- Patient samples revealed a positive correlation between IL-21 levels and CD8+ T cell infiltration after radiotherapy.

## 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.

IL-21 combined with radiation boosted anti-tumor efficacy via increased infiltration and boosted function of intratumoral CD8+ T cells, providing experimental evidence for clinical employment of IL-21 as an immunomodulator combined with radiotherapy.