Hematopoietic stem and progenitor cells overcome treatment resistance to immune checkpoint inhibitors in preclinical gliomas 2240834

Abstract

Abstract Introduction Glioblastoma (GBM) is one of the most lethal primary brain tumors, with dismal survival. Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, with efficacy shown in several solid tumors, yet its impact in GBM has been dismal. To overcome this treatment resistance, we developed a combinatorial strategy incorporating hematopoietic stem and progenitor cells (HSPCs) , whole brain radiation therapy (WBRT), and ICI with either αCTLA-4 or αVISTA in a syngeneic murine glioma model that is completely unresponsive to ICIs. However, our combination therapy significantly prolonged survival in glioma-bearing mice compared to controls. These findings support the potential of multi-pronged immunotherapeutic strategies to improve outcomes in glioma and highlight VISTA and CTLA-4 as promising targets. Methods C57BL/6 mice received orthotopic KR158B gliomas followed by WBRT at 9 Gy single dose. Bone marrow-derived lineage- HSPCs were isolated and co-transferred with ICI, either 100ug loading dose of αCTLA-4 or 30ug αVISTA. Results Our data demonstrated a significant survival benefit using the combinatorial therapy of HSPC + WBRT + αCTLA-4, with over 50% of the glioma-bearing mice surviving beyond 150 days. Similarly, HSPC + WBRT + αVISTA also led to a significant survival advantage compared to control groups. Conclusion The use if HSPCs in combination with ICI remarkably resets the immune system to allow the efficacy of ICI in otherwise treatment resistance gliomas. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)