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

Mathieu Gigoux, Morten O. Holmström, Roberta Zappasodi, Joseph J. Park, Stephane Pourpe, Cansu Cimen Bozkus, Levi M.B. Mangarin, David Redmond, Svena Verma, Sara Schad, Mariam M. George, Divya Venkatesh, Arnab Ghosh, David Hoyos, Zaki Molvi, Baransel Kamaz, Anna E. Marneth, William Duke, Matthew J. Leventhal, Max JanVincent T. Ho, Gabriela S. Hobbs, Trine Alma Knudsen, Vibe Skov, Lasse Kjær, Thomas Stauffer Larsen, Dennis Lund Hansen, R. Coleman Lindsley, Hans Hasselbalch, Jacob H. Grauslund, Thomas L. Lisle, Özcan Met, Patrick Wilkinson, Benjamin Greenbaum, Manuel A. Sepulveda, Timothy Chan, Raajit Rampal, Mads H. Andersen, Omar Abdel-Wahab, Nina Bhardwaj, Jedd D. Wolchok, Ann Mullally, Taha Merghoub

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9 Scopus citations

Abstract

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT 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 CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT 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 CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide–based cancer vaccines in patients with CALRMUT MPN.

Original languageEnglish
Article numbereaba4380
JournalScience Translational Medicine
Volume14
Issue number649
DOIs
StatePublished - 15 Jun 2022

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