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- Title
Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.
- Authors
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
- 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. Producing peptides to activate T cells against MPN: Myeloproliferative neoplasms (MPNs) that have frameshift mutations in calreticulin (CALR) rarely have T cells that target this neoantigen. Gigoux et al. investigated the lack of these T cells by examining class I major histocompatiblity complex (MHC-I) allele frequencies in these patients. They saw a skewing of these alleles and thus developed a heteroclitic peptide vaccine to activate T cells against these tumors. They saw a response in patient samples ex vivo and in mice to immunization with this peptide, which represents a promising treatment for patients with this disease.
- Subjects
PEPTIDES; T cell receptors; CANCER vaccines; MYELOPROLIFERATIVE neoplasms; CALRETICULIN; T cells; MAJOR histocompatibility complex
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 649, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aba4380