ESTRO 2025 - Abstract Book

S3893

Radiobiology - Microenvironment

ESTRO 2025

1724

Digital Poster Clonal hematopoiesis induces immunosuppression in the tumor microenvironment after radiotherapy, promoting local recurrence Shotaro Tatekawa 1,2 , Daisuke Motooka 3 , Shohei Katsuki 4 , Keisuke Tamari 1 , Kazumasa Minami 4 , Yutaka Takahashi 4 , Hideshi Ishii 2 , Hidenori Inohara 5 , Kazuhiko Ogawa 1 1 1. Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan. 2 4. Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Osaka, Japan. 3 2. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. 4 3. Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Osaka, Japan. 5 5. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan Purpose/Objective: Clonal Hematopoiesis (CH) has emerged as a risk factor for atherosclerotic cardiovascular disease through macrophage-induced vascular endothelium activation 1 2 . Recent studies indicate CH-bearing lymphocytes infiltrate tumor tissue 3 and affect cancer patient survival 4 . We investigated the relationship between CH and radiotherapy resistance, focusing on its impact on the tumor microenvironment. Material/Methods: We conducted target sequencing of peripheral blood from head and neck cancer patients (n=67) before radiotherapy. Germline mutations were excluded using ToMMo 4.7kJPN database (allele frequency ≥1%). Clinical outcomes were compared between patients with and without CH. Additionally, we utilized hematopoietic cell specific Tet2 knockout mice (Tet2flox/flox × Vav-iCre) to evaluate CH effects on radiotherapy response in a subcutaneous tumor model. RNA sequencing analyzed tumor and non-tumor cells pre- and post-radiotherapy to assess CH's influence on the tumor microenvironment. Results: CH was detected in 27% of patients (18/67), with mutations primarily in TET2 (n=5), DNMT3A (n=3), PPM1D (n=3), and ASXL1 (n=2). While patient characteristics were comparable between groups except for age, multivariate analysis identified CH as a significant risk factor for reduced relapse-free survival and increased local recurrence. The Tet2 knockout mouse model demonstrated significantly enhanced tumor growth post-radiotherapy compared to wild-type controls. RNA sequencing revealed that CH (Tet2 knockout) promoted an immunosuppressive tumor microenvironment following radiotherapy, correlating with increased local recurrence. Conclusion: Our findings establish CH as a risk factor for local recurrence and reduced relapse-free survival post-radiotherapy in head and neck cancer patients. This effect appears mediated through the induction of an immunosuppressive tumor microenvironment. These results suggest that CH-positive patients may benefit from post-radiotherapy immune checkpoint inhibitor therapy. Future research will focus on elucidating the detailed mechanisms underlying CH-mediated radiotherapy resistance and developing strategies to mitigate CH-associated local recurrence. References: 1. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. The New England journal of medicine 2017;377:111-121. 2. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with tet2 deficiency accelerates atherosclerosis development in mice. Science (New York, NY) 2017;355:842-847. 3. Severson EA, Riedlinger GM, Connelly CF, et al. Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens. Blood 2018. Keywords: clonal hematopoiesis, tumor microenvironment