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

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  • 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 Jan
  • Vincent 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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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
Pages (from-to)eaba4380
ISSN1946-6234
DOIs
Publication statusPublished - 15 Jun 2022

ID: 79292482