Radiation induces iatrogenic immunosuppression by indirectly affecting hematopoiesis in bone marrow
Vaishali Kapoor, Andrea Collins, Kaylan Griffith, Subhajit Ghosh, Nathan Wong, Xiaowei Wang, Grant A. Challen, Joseph R. Krambs, Dan Link, Dennis E. Hallahan, Dinesh Thotala
Abstract
// Vaishali Kapoor 1 , Andrea Collins 1 , Kaylan Griffith 1 , Subhajit Ghosh 1 , Nathan Wong 1 , Xiaowei Wang 1 , Grant A. Challen 3 , Joseph Krambs 5 , Dan Link 3 , 4 , Dennis E. Hallahan 1 , 2 and Dinesh Thotala 1 , 2 1 Department of Radiation Oncology, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA 2 Siteman Cancer Center, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA 3 Department of Medicine, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA 4 Department of Pathology & Immunology, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA 5 Medical Scientist Training Program, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA Correspondence to: Dinesh Thotala, email: [email protected] Keywords: radiation; lymphopenia; mass cytometry RNA sequencing Received: October 14, 2019     Accepted: April 03, 2020     Published: May 12, 2020 ABSTRACT 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 are largely unknown. We found that irradiation not only had direct effects on circulating lymphocytes but also had indirect effects on the spleen, thymus, and bone marrow. We found that irradiated cells traffic to the bone marrow and bring about the reduction of hematopoietic stem cells (HSC) and progenitor cells. Using mass cytometry analysis (CyTOF) of the bone marrow, we found reduced expression of CD11a, which is required for T cell proliferation and maturation. RNA Sequencing and gene set enrichment analysis of the bone marrow cells following irradiation showed down-regulation of genes involved in hematopoiesis. Identification of CD11a and hematopoietic genes involved in iatrogenic immune suppression can help identify mechanisms of RIL.