Anti-leukemia immunity is enabled by unmasking cross-reactive antigens with vaccination and checkpoint blockade
2015-12
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Anti-leukemia immunity is enabled by unmasking cross-reactive antigens with vaccination and checkpoint blockade
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2015-12
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BCR-ABL+ acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific antigen that could be a target for immunotherapy. To address how BCR-ABL+ leukemia escapes immune surveillance, we developed a peptide: MHC-II tetramer that labels endogenous BCR-ABL-specific CD4+ T cells. Naïve mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. We saw that BCR-ABL specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL+ leukemia, BCR-ABL specific T cells proliferated and converted into regulatory T cells (Treg cells), a process that was dependent on cross-reactivity with self-antigen, TGFβ1, and MHC-II antigen presentation by leukemic cells. Treg cells were critical for leukemia progression in C57Bl/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. In an effort to find immunotherapy approaches for BCR-ABL+ B-ALL, we found that robust MHC-II expression, coupled with appropriate costimulation, correlated with lower leukemic burden. We next assessed whether checkpoint blockade or therapeutic vaccination could improve survival in mice with pre-established leukemia. Consistent with the low mutation load in our leukemia model, we found that checkpoint blockade alone had only modest effects on survival. In contrast, robust heterologous vaccination with BAp peptide generated a small population of mice that survived long-term. Checkpoint blockade strongly synergized with heterologous vaccination to enhance overall survival in mice with leukemia. Enhanced survival did not correlate with numbers of BAp:I-Ab-specific T cells, but rather with increased expression of IL10, IL17, and GrzmB and decreased expression of PD1 on these cells. Thus, despite a paradigm in the field that numerous neo-antigen specific T cells are required for effective anti-cancer immunity, a rare cross-reactive CD4+ T cell population mediates anti-leukemia immunity in our model.
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University of Minnesota Ph.D. dissertation. December 2015. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Michael Farrar. 1 computer file (PDF); xvii, 206 pages.
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Manlove, Luke. (2015). Anti-leukemia immunity is enabled by unmasking cross-reactive antigens with vaccination and checkpoint blockade. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/177132.
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