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

Authors: Gigoux, M.; Holmström, M. O.; Zappasodi, R.; Park, J. J.; Pourpe, S.; Bozkus, C. C.; Mangarin, L. M. B.; Redmond, D.; Verma, S.; Schad, S.; George, M. M.; Venkatesh, D.; Ghosh, A.; Hoyos, D.; Molvi, Z.; Kamaz, B.; Marneth, A. E.; Duke, W.; Leventhal, M. J.; Jan, M.; Ho, V. T.; Hobbs, G. S.; Knudsen, T. A.; Skov, V.; Kjær, L.; Larsen, T. S.; Hansen, D. L.; Lindsley, R. C.; Hasselbalch, H.; Grauslund, J. H.; Lisle, T. L.; Met, Ö; Wilkinson, P.; Greenbaum, B.; Sepulveda, M. A.; Chan, T.; Rampal, R.; Andersen, M. H.; Abdel-Wahab, O.; Bhardwaj, N.; Wolchok, J. D.; Mullally, A.; Merghoub, T.
Article Title: Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine
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.
Keywords: myeloproliferative disorders; genetics; mutation; myeloproliferative disorder; janus kinase 2; neoplasm; neoplasms; mouse; animal; animals; mice; peptide; mice, inbred c57bl; c57bl mouse; cancer vaccine; cancer vaccines; peptides; major histocompatibility complex; vaccines, subunit; subunit vaccine; calreticulin; humans; human
Journal Title: Science Translational Medicine
Volume: 14
Issue: 649
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2022-06-15
Start Page: eaba4380
Language: English
DOI: 10.1126/scitranslmed.aba4380
PUBMED: 35704596
PROVIDER: scopus
Notes: Article -- Export Date: 1 July 2022 -- Source: Scopus
Citation Impact
MSK Authors
  1. Timothy Chan
    308 Chan
  2. Jedd D Wolchok
    853 Wolchok
  3. Taha Merghoub
    319 Merghoub
  4. Raajit Kumar Rampal
    222 Rampal
  5. Arnab Ghosh
    58 Ghosh
  6. Stephane Pourpe
    11 Pourpe
  7. Mathieu Gigoux
    18 Gigoux
  8. Sara Schad
    13 Schad
  9. David Hoyos
    10 Hoyos
  10. Svena Verma
    8 Verma
  11. Zaki Molvi
    5 Molvi
  12. Joseph J Park
    1 Park
  13. Mariam Mathew George
    2 George