Therapeutic cancer vaccination against mutant calreticulin in myeloproliferative neoplasms induces expansion of specific T cells in the periphery but specific T cells fail to enrich in the bone marrow.

Autor:	Holmström MO; National Center for Cancer Immune Therapy, Department of Oncology, Herlev University Hospital, Herlev, Denmark.; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Andersen M; Centre for Mathematical Modeling - Human Health and Disease, IMFUFA, Department of Science and Environment, Roskilde University, Roskilde, Denmark., Traynor S; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Ahmad SM; National Center for Cancer Immune Therapy, Department of Oncology, Herlev University Hospital, Herlev, Denmark., Lisle TL; National Center for Cancer Immune Therapy, Department of Oncology, Herlev University Hospital, Herlev, Denmark., Handlos Grauslund J; National Center for Cancer Immune Therapy, Department of Oncology, Herlev University Hospital, Herlev, Denmark., Skov V; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Kjær L; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Ottesen JT; Centre for Mathematical Modeling - Human Health and Disease, IMFUFA, Department of Science and Environment, Roskilde University, Roskilde, Denmark., Gjerstorff MF; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Department of Oncology, Odense University Hospital, Odense, Denmark., Hasselbalch HC; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Andersen MH; National Center for Cancer Immune Therapy, Department of Oncology, Herlev University Hospital, Herlev, Denmark.; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Aug 17; Vol. 14, pp. 1240678. Date of Electronic Publication: 2023 Aug 17 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1240678
Abstrakt:	Background: Therapeutic cancer vaccination against mutant calreticulin ( CALR ) in patients with CALR -mutant ( CALR mut) myeloproliferative neoplasms (MPN) induces strong T-cell responses against mutant CALR yet fails to demonstrate clinical activity. Infiltration of tumor specific T cells into the tumor microenvironment is needed to attain a clinical response to therapeutic cancer vaccination. Aim: Determine if CALRmut specific T cells isolated from vaccinated patients enrich in the bone marrow upon completion of vaccination and explore possible explanations for the lack of enrichment. Methods: CALRmut specific T cells from four of ten vaccinated patients were expanded, enriched, and analyzed by T-cell receptor sequencing (TCRSeq). The TCRs identified were used as fingerprints of CALRmut specific T cells. Bone marrow aspirations from the four patients were acquired at baseline and at the end of trial. T cells were enriched from the bone marrow aspirations and analyzed by TCRSeq to identify the presence and fraction of CALRmut specific T cells at the two different time points. In silico calculations were performed to calculate the ratio between transformed cells and effector cells in patients with CALR mut MPN. Results: The fraction of CALRmut specific T cells in the bone marrow did not increase upon completion of the vaccination trial. In general, the T cell repertoire in the bone marrow remains relatively constant through the vaccination trial. The enriched and expanded CALRmut specific T cells recognize peripheral blood autologous CALR mut cells. In silico analyses demonstrate a high imbalance in the fraction of CALR mut cells and CALRmut specific effector T-cells in peripheral blood. Conclusion: CALRmut specific T cells do not enrich in the bone marrow after therapeutic cancer peptide vaccination against mutant CALR. The specific T cells recognize autologous peripheral blood derived CALR mut cells. In silico analyses demonstrate a high imbalance between the number of transformed cells and CALRmut specific effector T-cells in the periphery. We suggest that the high burden of transformed cells in the periphery compared to the number of effector cells could impact the ability of specific T cells to enrich in the bone marrow. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Holmström, Andersen, Traynor, Ahmad, Lisle, Handlos Grauslund, Skov, Kjær, Ottesen, Gjerstorff, Hasselbalch and Andersen.)
Databáze:	MEDLINE
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