444 MHC-I skewing in mutant calreticulin-positive myeloproliferative neoplasms is countered by heteroclitic peptide cancer vaccination
Year: 2020
Type: conference-abstract
Abstract: Background The majority of JAK2V617F-negative myeloproliferative neoplasms (MPN) have disease-initiating frameshift mutations in calreticulin (CALR) resulting in a common novel C-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 CALRMUT MPN patients, but the underlying reasons for this phenomenon are unknown. Methods In this study, we examine class-I major histocompatibility complex (MHC-I) allele frequency in CALRMUT MPN patients from two independent cohorts and observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are under-represented in CALRMUT MPN patients. We speculate that this is 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 manifests. As a consequence of this MHC-I allele restriction, we reasoned that CALRMUT MPN patients would not efficiently respond to cancer vaccines composed of the CALRMUT fragment, but could do so when immunized with a properly modified CALRMUT heteroclitic peptide vaccine approach. Results We found that heteroclitic CALRMUT peptides specifically designed for CALRMUT MPN patient MHC-I alleles efficiently elicited a cross-reactive CD8+ T cell response in human PBMC samples otherwise unable to respond to the matched weakly immunogenic CALRMUT native peptides. We also modeled this effect in mice and observed that C57BL/6J mice, which are unable to mount an immune response to the human CALRMUT fragment, can mount a cross-reactive CD8+ T cell response against a CALRMUT-derived peptide upon heteroclitic peptide immunization and this was further amplified by combining the heteroclitic peptide vaccine with blockade of the immune checkpoint molecule PD-1. Conclusions Together, our data underscore the therapeutic potential of heteroclitic peptide-based cancer vaccines in CALRMUT MPN patients. Ethics Approval Approval was obtained for the use of patient-derived specimens and access to clinical data extracted from patient charts by the Institutional Review Boards at Memorial Sloan Kettering Cancer Center, the Dana-Farber Cancer Institute and the Massachusetts General Hospital, as well as by the Danish Regional Science Ethics Committee. Mouse experiments were performed in accordance with institutional guidelines under a protocol approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee.
Authors: Mathieu Gigoux, Roberta Zappasodi, Joseph Park, Stephane Pourpe, Arnab Ghosh, Cansu Cimen Bozkus, Levi Mangarin, David Redmond, Svena Verma, Sara Schad, William Duke, Max Jan, Matthew Leventhal, Vincent Ho, Gabriela Hobbs, Trine Alma Knudsen, Vibe Skov, Lasse Kjær, Thomas Stauffer Larsen, Dennis Lund Hansen, R Coleman Lindsley, Hans Hasselbalch, Jacob Grauslund, Mads Andersen, Morten Holmström, Timothy Chan, Raajit Rampal, Omar Abdel-Wahab, Nina Bhardwaj, Jedd Wolchok, Ann Mullally, Taha Merghoub
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Funders: EMD Serono, National Cancer Institute
OpenAlex ID: W3102763483