ESTRO 2025 - Abstract Book

S3880

Radiobiology - Immuno-radiobiology

ESTRO 2025

2639

Proffered Paper The CCR7-CCL19/CCL21 immune cell homing axis in response to irradiation Sabrina Reichl 1,2 , Irma Telarovic 1,2 , Lisa Kurz 3 , Alba Sanchez Fernandez 1 , Irene Vetrugno 1 , Martin Pruschy 1 1 Laboratory for Applied Radiobiology, University of Zurich, Zurich, Switzerland. 2 Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland. 3 Institute of Immunobiology, Medical Research Center, Kantonsspital St. Gallen, St. Gallen, Switzerland Purpose/Objective: Immune checkpoint inhibitors (ICI) have revolutionized modern oncology by achieving durable responses in previously treatment-resistant cancers. The propensity of radiotherapy to act as an in situ tumor vaccine motivated the introduction of radiotherapy-ICI combinations to overcome treatment resistance. Yet, clinical outcomes have not met expectations. Common practice of concomitant lymph node irradiation is one of the major culprits, as lymph nodes are crucial for the cancer-immunity cycle and for the vaccination effect of radiotherapy. At the same time, lymph nodes are a common site of early metastatic spread, making sparing them infeasible for patients with nodal metastases 1,2,3 . Using murine tumor models, our group demonstrated delayed (adjuvant) lymph node irradiation as a highly promising approach to maximize radioimmunotherapy efficacy. Moreover, we identified disruption of the CCR7 CCL19/CCL21 immune cell homing axis upon tumor-draining lymph node irradiation 4 . Here, we aimed to conduct a more thorough investigation into irradiation-induced functional and structural changes in the lymph node to improve our understanding of the communication between the irradiated tumor and the draining lymph node. Material/Methods: In vivo irradiated lymph nodes of C57BL/6 mice were analyzed for multiplex cytokine assessment, flow cytometry based immunophenotyping and immunohistochemical staining. Results: Quantitative chemokine analysis on day 2 post-irradiation revealed a significant decrease of CCL19 and CCL21 in lymph nodes irradiated with 10, 15 and 20 Gy, but not 2 or 5 Gy, when compared to sham-irradiated lymph nodes. Concurrently, immunophenotyping of irradiated lymph nodes on day 2 post-irradiation showed reduced numbers of lymphocytes, regardless of the dose applied. By day 9, irradiated lymph nodes partially recovered from both lymphopenia and CCL19/CCL21 downregulation. However, lymphopenia in response to a single high dose of irradiation remained evident in the lymph nodes through day 100 post-irradiation. Consistently, structural changes were observed within the stromal cell network of the irradiated lymph nodes. Conclusion: The homeostatic chemokines CCL19 and CCL21, which are constitutively produced by lymph node stromal cells, guide the migration of CCR7 receptor-expressing T cells into lymph nodes. Our findings suggest dose-dependent irradiation-induced functional and structural changes in the stromal cell subsets, relevant for the integrity of the CCR7-CCL19/CCL21 axis. A disrupted axis might subsequently result in the inability of the lymph node to resume critical draining lymph node-to-tumor communication and to reinstall lymph node functionality.

Keywords: Lymph node irradiation, CCL19, stromal cells

References: 1. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y.-X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14 , 365–379 (2017). 2. Pointer, K. B., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 8 , 9–20 (2022).