Checkpoint blockade-based immunotherapies are effective in cancers with high numbers of nonsynonymous mutations. In contrast, current paradigms suggest that such approaches will be ineffective in cancers with few nonsynonymous mutations. To examine this issue, we made use of a murine model of BCR-ABL+ B-lineage acute lymphoblastic leukemia. Using a principal component analysis, we found that robust MHC class 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 preestablished 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 a peptide derived from the BCR-ABL fusion (BAp), a key driver mutation, 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 IL-10, IL-17, and granzyme B and decreased expression of programmed death 1 on these cells. Our findings demonstrate that vaccination to key driver mutations cooperates with checkpoint blockade and allows for immune control of cancers with low nonsynonymous mutation loads.
Bibliographical noteFunding Information:
This work was supported in part by National Institutes of Health Grant P30CA77598, which supports the University of Minnesota Flow Cytometry Resource. L.S.M. and J.M.S. are supported by National Institutes of Health Fellowships F31CA183226 and F30DK100159, respectively. K.R.M. is supported by a Pennsylvania State University academic computing fellowship. K.E.P. is supported by the Robertson Foundation/Cancer Research Institute Irvington Fellowship. M.A.F. is supported by National Institutes of Health Grants R01CA151845, R01CA154998, R56AI113138, and R01CA185062, the University of Minnesota Masonic Cancer Center, and a Leukemia and Lymphoma Society Scholar Award.
Copyright © 2016 by The American Association of Immunologists, Inc.