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bioRxiv · 10.1101/2024.12.21.629902

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

Venkatesh, H.·Heltemes-Harris, L.·Arroyo, M.·Knutson, T. P.·Qiu, Y.·Haaning, A. M.·Webber, B. R.·Bachanova, V.·Farrar, M. A.·Tracy, S.
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Abstract

The significance of endogenous immune surveillance in acute lymphoblastic leukemia (ALL) remains controversial. Using clinical B-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. Tr1s then inhibit cytotoxic CD8+ T cells, preventing effective leukemia clearance. Leukemic cells induce Tr1s 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, inhibition of Tr1 expansion with IL10 receptor (IL10R) blockade is 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 towards Th1 states. Our findings uncover a mechanism that enables leukemic relapse and resolves existing controversies on the role of immune surveillance towards this cancer type. Therapeutic polarization of neoantigen-specific CD4+ T cells towards Th1 states may improve contemporary immune therapies by reshaping the immune microenvironment towards states permissive for cytotoxic attack of residual leukemia. Key PointsO_LIB-ALL induces neoantigen-specific CD4+ T cells to adopt Type-1 regulatory states, which protect leukemic cells from immune pressure. C_LIO_LIRepolarizing neoantigen-specific CD4+ T-cells towards Th1 states eradicates measurable residual disease. C_LI

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Venkatesh, H., Heltemes-Harris, L., Arroyo, M., Knutson, T. P., Qiu, Y., Haaning, A. M., Webber, B. R., Bachanova, V., Farrar, M. A., Tracy, S.. 2024-12-22. Leukemia escapes immunity by imposing a Type-1 regulatory program on neoantigen-specific CD4+ T cells.. https://doi.org/10.1101/2024.12.21.629902

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