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
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85132078731&doi=10.1126%2fscitranslmed.aba4380&partnerID=40&md5=ded7e821b12a65f3db1e0f79a8e0d2a9
Notes:	Article -- Export Date: 1 July 2022 -- Source: Scopus