The majority of JAK2 V617F -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( CALR ), resulting in a common carboxyl-terminal mutant fragment (CALR MUT ), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR MUT -specific T cells are rare in patients with CALR MUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR MUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALR MUT neoepitopes with high affinity are underrepresented in patients with CALR MUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALR MUT MPN would not efficiently respond to a CALR MUT fragment cancer vaccine but would when immunized with a modified CALR MUT heteroclitic peptide vaccine approach. We found that heteroclitic CALR MUT peptides specifically designed for the MHC-I alleles of patients with CALR MUT MPN efficiently elicited a CALR MUT cross-reactive CD8 + T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR MUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8 + T cell response to the CALR MUT fragment upon immunization with a CALR MUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide–based cancer vaccines in patients with CALR MUT MPN.

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine

Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Human Oncology and Pathogenesis Program and Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Department of Oncology, National Center for Cancer Immune Therapy, Herlev Hospital, Herlev 2730, Denmark.

Department of Immunology and Microbiology, Copenhagen University Hospital, Herlev 2730, Denmark.

Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.

Weill Cornell Medical College, New York, NY 10065, USA.

Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Division of Regenerative Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA.

Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Computational Oncology, Department of Epidemiology &amp; Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Weill Cornell Medicine, New York, NY 10065, USA.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Department of Medicine, Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

Broad Institute, Cambridge, MA 02142, USA.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Department of Hematology, Zealand University Hospital, Roskilde 4000, Denmark.

Department of Hematology, Odense University Hospital, Odense 5000, Denmark.

Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson &amp; Johnson, Spring House, PA 19002, USA.

Weill Cornell Medicine, Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA.

Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Parker Institute for Cancer Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.