B cell leukemia elicits a suppressive Tr1-like CD4 T cell response that can be reversed with anti-PDL1-blockade

Abstract CD4 T cell exhaustion is associated with relapse in B leukemia (B-ALL) patients. However, checkpoint blockade not effective treating B-ALL. Using a murine model of B-ALL, we demonstrate that induced cells had unique regulatory-cytotoxic phenotype (T rctx) preferential expression markers (PD1/TIM3) as well IL10 and c-Maf, which are immunosuppressive Tr1 cells. Leukemia acting APCs elicited similar suppressed bystander This process mimics the mechanism by hematopoietic stem (HSC) enforce an niche bone marrow protects HSC compartment. Anti-PDL1 ornilotinib (targeted therapy) treatment alone minimal impact on survival; concurrent anti-PDL1 andnilotinib significant synergistic effect was dependent CD8 Nilotinib increased helper regulatory function rctxcells. In contrast, nilotinib andanti-PDL1 expansion leukemia-specific clone lower higher molecules facilitate recruitment activation anti-tumor immune Expansion helper-cytotoxic hctx) GzmB +CD8 We propose coopts naturally occurring designed to protect niche, thereby inducing rctxcells drive escape from surveillance. Combining alters balance between rctxand immune-activating hctx, protective anti-leukemia response prevents relapse. Spatial Transcriptomics Award University Minnesota, Children's Cancer Research Fund