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

The majority of JAK2 -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( ), resulting in a common carboxyl-terminal mutant fragment (CALR ), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that...

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Vydané v:	Science translational medicine Ročník 14; číslo 649; s. eaba4380
Hlavní autori:	Gigoux, Mathieu, Holmström, Morten O, Zappasodi, Roberta, Park, Joseph J, Pourpe, Stephane, Bozkus, Cansu Cimen, Mangarin, Levi M B, Redmond, David, Verma, Svena, Schad, Sara, George, Mariam M, Venkatesh, Divya, Ghosh, Arnab, Hoyos, David, Molvi, Zaki, Kamaz, Baransel, Marneth, Anna E, Duke, William, Leventhal, Matthew J, Jan, Max, Ho, Vincent T, Hobbs, Gabriela S, Knudsen, Trine Alma, Skov, Vibe, Kjær, Lasse, Larsen, Thomas Stauffer, Hansen, Dennis Lund, Lindsley, R Coleman, Hasselbalch, Hans, Grauslund, Jacob H, Lisle, Thomas L, Met, Özcan, Wilkinson, Patrick, Greenbaum, Benjamin, Sepulveda, Manuel A, Chan, Timothy, Rampal, Raajit, Andersen, Mads H, Abdel-Wahab, Omar, Bhardwaj, Nina, Wolchok, Jedd D, Mullally, Ann, Merghoub, Taha
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.06.2022
Predmet:	Animals Calreticulin - genetics Cancer Vaccines Humans Janus Kinase 2 - genetics Major Histocompatibility Complex Mice Mice, Inbred C57BL Mutation - genetics Myeloproliferative Disorders - genetics Neoplasms - genetics Peptides Vaccines, Subunit
ISSN:	1946-6242, 1946-6242
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Shrnutí:	The majority of JAK2 -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( ), resulting in a common carboxyl-terminal mutant fragment (CALR ), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR -specific T cells are rare in patients with CALR MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR MPN from two independent cohorts. We observed that MHC-I alleles that present CALR neoepitopes with high affinity are underrepresented in patients with CALR 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 MPN would not efficiently respond to a CALR fragment cancer vaccine but would when immunized with a modified CALR heteroclitic peptide vaccine approach. We found that heteroclitic CALR peptides specifically designed for the MHC-I alleles of patients with CALR MPN efficiently elicited a CALR cross-reactive CD8 T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR 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 fragment upon immunization with a CALR heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALR MPN.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1946-6242 1946-6242
DOI:	10.1126/scitranslmed.aba4380