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- W4385687064 abstract "Abstract CD4 T cell exhaustion is associated with relapse in B cell leukemia (B-ALL) patients. However, checkpoint blockade is not effective in treating B-ALL. Using a murine model of B-ALL, we demonstrate that leukemia induced CD4 T cells had a unique regulatory-cytotoxic phenotype (T rctx) with preferential expression of exhaustion markers (PD1/TIM3) as well as IL10 and c-Maf, which are markers of immunosuppressive Tr1 cells. Leukemia cells acting as APCs elicited CD4 T cells with a similar Tr1 phenotype that suppressed bystander T cells. This process mimics the mechanism by which hematopoietic stem cells (HSC) enforce an immunosuppressive niche in the bone marrow that protects the HSC compartment. Anti-PDL1 ornilotinib (targeted therapy) treatment alone had a minimal impact on survival; concurrent treatment with anti-PDL1 andnilotinib had a significant synergistic effect that was dependent on CD4 and CD8 T cells. Nilotinib treatment increased markers of helper and regulatory function in the T rctxcells. In contrast, treatment with nilotinib andanti-PDL1 induced expansion of a leukemia-specific CD4 T cell clone with lower expression of Tr1 markers and higher expression of helper molecules that facilitate recruitment and activation of anti-tumor immune cells. Expansion of the helper-cytotoxic (T hctx) CD4 T cell clone was associated with increased GzmB +CD8 T cells. We propose that leukemia coopts a naturally occurring process designed to protect the HSC niche, thereby inducing T rctxcells that drive escape from immune surveillance. Combining nilotinib and anti-PDL1 alters the balance between immunosuppressive T rctxand immune-activating T hctx, thereby inducing a protective anti-leukemia immune response that prevents relapse. Spatial Transcriptomics Award from the University of Minnesota, Children's Cancer Research Fund" @default.
- W4385687064 created "2023-08-10" @default.
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- W4385687064 date "2023-05-01" @default.
- W4385687064 modified "2023-10-02" @default.
- W4385687064 title "B cell leukemia elicits a suppressive Tr1-like CD4 T cell response that can be reversed with anti-PDL1-blockade" @default.
- W4385687064 doi "https://doi.org/10.4049/jimmunol.210.supp.230.03" @default.
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