CD4 T cell dysfunction and leukemic quiescence promote immune tolerance in B-cell acute lymphoblastic leukemia 2890

Abstract Description Treatments for B-Cell Acute Lymphoblastic Leukemia (B-ALL) have improved but relapse remains a major problem. Recent studies have shown that the presence of CD4+PD1+TIM3+ T cells is the strongest immune correlate with relapse. We have observed a similar phenomenon in a mouse model of B-ALL and shown that these CD4+TIM3+ cells are IL10+ Type I regulatory T cells (Tr1) cells. Targeted treatment of leukemic mice with nilotinib results in a transient reduction of leukemia but a further accumulation of suppressive Tr1 cells. In contrast, treatment with nilotinib plus anti-PDL1 reduced Tr1s and led to the emergence of CX3CR1+AHNAK+ Th1 cells that correlated with leukemia elimination. We propose that quiescent leukemia cells induce Tr1 differentiation in a MHCII-dependent manner. Supporting this idea, we found that in untreated leukemic mice around 10% of leukemic cells were Ki67-MHCII+. Treatment with nilotinib eliminated >90% of leukemic cells; residual leukemic cells were almost all MHCII+, which correlated with an increase in leukemia specific Tr1 cells. Preliminary histology results suggest that this may correlate with preferential localization of leukemia from the splenic red pulp to the T:B border within the white pulp; this relocalization is disrupted by anti-PDL1 treatment. Our findings suggest that Ki67-MHCII+ leukemic cells entrain immunosuppressive Tr1 induction in an MHCII+ manner allowing for immune escape, but this can be reversed or overcome by PDL1 blockade. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)