Leukemia escapes immunity by imposing a type 1 regulatory program on neoantigen-specific CD4⁺T cells

The significance of endogenous immune surveillance in acute lymphoblastic leukemia (ALL) remains controversial. Using clinical B-cell ALL samples and a novel mouse model, we show that neoantigen-specific CD4⁺T cells are induced to adopt type 1 regulatory (Tr1) function in the leukemia microenvironment. Tr1 cells then inhibit cytotoxic CD8⁺T cells, preventing effective leukemia clearance. Leukemic cells induce Tr1 cells by phenocopying hematopoietic stem cells, which normally are subject to effective surveillance by this CD4⁺subset. This mechanism effectively redirects Tr1 cells from a role in preventing cancer to maladaptively promoting clinical relapse. In mouse models, addition of interleukin-10 receptor (IL-10R) blockade to cytotoxic therapy modestly affected Tr1 development but was insufficient to improve leukemia control. In contrast, combined therapy with a cytotoxic agent and anti-PDL1 blockade eradicated measurable residual disease. This correlates with polarization of the neoantigen-specific CD4⁺T-cell population from Tr1 toward T helper 1 (Th1) states. Our findings uncover a mechanism that enables leukemic relapse and resolves existing controversies on the role of immune surveillance toward this cancer type. Therapeutic polarization of neoantigen-specific CD4⁺T cells away from Tr1 and toward Th1 states may improve contemporary immune therapies by reshaping the immune microenvironment toward states permissive for cytotoxic attack of residual leukemia.