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

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Harvard

Gigoux, M, Holmström, MO, Zappasodi, R, Park, JJ, Pourpe, S, Bozkus, CC, Mangarin, LMB, Redmond, D, Verma, S, Schad, S, George, MM, Venkatesh, D, Ghosh, A, Hoyos, D, Molvi, Z, Kamaz, B, Marneth, AE, Duke, W, Leventhal, MJ, Jan, M, Ho, VT, Hobbs, GS, Knudsen, TA, Skov, V, Kjær, L, Larsen, TS, Hansen, DL, Lindsley, RC, Hasselbalch, H, Grauslund, JH, Lisle, TL, Met, Ö, Wilkinson, P, Greenbaum, B, Sepulveda, MA, Chan, T, Rampal, R, Andersen, MH, Abdel-Wahab, O, Bhardwaj, N, Wolchok, JD, Mullally, A & Merghoub, T 2022, 'Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine', Science translational medicine, bind 14, nr. 649, eaba4380, s. eaba4380. https://doi.org/10.1126/scitranslmed.aba4380

APA

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., ... Merghoub, T. (2022). Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine. Science translational medicine, 14(649), eaba4380. [eaba4380]. https://doi.org/10.1126/scitranslmed.aba4380

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@article{5d11bf1799a54791afd6a5dbc07a8184,
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.",
author = "Mathieu Gigoux and Holmstr{\"o}m, {Morten O.} and Roberta Zappasodi and Park, {Joseph J.} and Stephane Pourpe and Bozkus, {Cansu Cimen} and Mangarin, {Levi M.B.} and David Redmond and Svena Verma and Sara Schad and George, {Mariam M.} and Divya Venkatesh and Arnab Ghosh and David Hoyos and Zaki Molvi and Baransel Kamaz and Marneth, {Anna E.} and William Duke and Leventhal, {Matthew J.} and Max Jan and Ho, {Vincent T.} and Hobbs, {Gabriela S.} and Knudsen, {Trine Alma} and Vibe Skov and Lasse Kj{\ae}r and Larsen, {Thomas Stauffer} and Hansen, {Dennis Lund} and Lindsley, {R. Coleman} and Hans Hasselbalch and Grauslund, {Jacob H.} and Lisle, {Thomas L.} and {\"O}zcan Met and Patrick Wilkinson and Benjamin Greenbaum and Sepulveda, {Manuel A.} and Timothy Chan and Raajit Rampal and Andersen, {Mads H.} and Omar Abdel-Wahab and Nina Bhardwaj and Wolchok, {Jedd D.} and Ann Mullally and Taha Merghoub",
year = "2022",
month = jun,
day = "15",
doi = "10.1126/scitranslmed.aba4380",
language = "English",
volume = "14",
pages = "eaba4380",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "649",

}

RIS

TY - JOUR

T1 - Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine

AU - Gigoux, Mathieu

AU - Holmström, Morten O.

AU - Zappasodi, Roberta

AU - Park, Joseph J.

AU - Pourpe, Stephane

AU - Bozkus, Cansu Cimen

AU - Mangarin, Levi M.B.

AU - Redmond, David

AU - Verma, Svena

AU - Schad, Sara

AU - George, Mariam M.

AU - Venkatesh, Divya

AU - Ghosh, Arnab

AU - Hoyos, David

AU - Molvi, Zaki

AU - Kamaz, Baransel

AU - Marneth, Anna E.

AU - Duke, William

AU - Leventhal, Matthew J.

AU - Jan, Max

AU - Ho, Vincent T.

AU - Hobbs, Gabriela S.

AU - Knudsen, Trine Alma

AU - Skov, Vibe

AU - Kjær, Lasse

AU - Larsen, Thomas Stauffer

AU - Hansen, Dennis Lund

AU - Lindsley, R. Coleman

AU - Hasselbalch, Hans

AU - Grauslund, Jacob H.

AU - Lisle, Thomas L.

AU - Met, Özcan

AU - Wilkinson, Patrick

AU - Greenbaum, Benjamin

AU - Sepulveda, Manuel A.

AU - Chan, Timothy

AU - Rampal, Raajit

AU - Andersen, Mads H.

AU - Abdel-Wahab, Omar

AU - Bhardwaj, Nina

AU - Wolchok, Jedd D.

AU - Mullally, Ann

AU - Merghoub, Taha

PY - 2022/6/15

Y1 - 2022/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85132078731&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aba4380

DO - 10.1126/scitranslmed.aba4380

M3 - Journal article

C2 - 35704596

AN - SCOPUS:85132078731

VL - 14

SP - eaba4380

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 649

M1 - eaba4380

ER -

ID: 79292482