Radiation Induces Iatrogenic Immunosuppression by Indirectly Affecting Hematopoiesis in Bone Marrow

Abstract

Background: The immune system plays a vital role in cancer therapy, especially with the advent of immunotherapy. Radiation therapy induces iatrogenic immunosuppression referred to as radiation-induced lymphopenia (RIL). RIL correlates with significant decreases in the overall survival of cancer patients. Although the etiology and severity of lymphopenia are known, the mechanism(s) of RIL is mainly unknown. Methods: PBMCs from various treatments were stained with anti-CD3, CD4, CD8, and CD19 antibodies and analyzed by MACSQuant Analyzer flow cytometer. Mass cytometry analysis (CyTOF) of the bone marrow was done to identify various cell populations. RNA Sequencing and gene set enrichment analysis of the bone marrow cells was done to identify genes involved in hematopoiesis. Findings: We found that irradiation not only had direct effects on circulating lymphocytes but also had a indirect impact on the spleen, thymus, and bone marrow. We discovered that irradiated cells traffic to the bone marrow, fuse with hematopoietic stem cells (HSC) and progenitor cells, and contributes to lymphocyte reduction. We found reduced expression of CD11a, which is required for T cell proliferation and maturation. We found down-regulation of genes involved in hematopoiesis using RNA Sequencing and gene set enrichment analysis. Interpretation: We found that irradiation had indirect effects on the bone marrow. We identified CD11a, and hematopoietic genes to be involved in iatrogenic immune suppression. Funding Statement: This project was supported by grants from Department of Radiation Oncology (Dinesh Thotala), National Institutes of Health; R01 CA174966 (Dennis Hallahan), R01 DK102428 (Grant A Challen). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All studies were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee and with protocols approved by the Washington University Division of Comparative Medicine.