2. Academic Validation
  3. Oncogenic Calreticulin Induces Immune Escape by Stimulating TGF-β Expression and Regulatory T Cell Expansion in the Bone Marrow Microenvironment

Oncogenic Calreticulin Induces Immune Escape by Stimulating TGF-β Expression and Regulatory T Cell Expansion in the Bone Marrow Microenvironment

  • Cancer Res. 2024 Jun 17. doi: 10.1158/0008-5472.CAN-23-3553.
Dominik Schmidt 1,  Cornelia Endres 2,  Rouven Hoefflin 3,  Geoffroy Andrieux 4,  Melissa Zwick 5,  Nikolaos Karantzelis 1,  Hans F Staehle 1,  Janaki Manoja Vinnakota 1,  Sandra Duquesne 6,  Miriam Mozaffari Jovein 1,  Dietmar Pfeifer 5,  Heiko Becker 1,  Bruce R Blazar 7,  Alexander Zähringer 1,  Justus Duyster 8,  Tilman Brummer 9,  Melanie Boerries 9,  Julian Baumeister 10,  Khalid Shoumariyeh 11,  Juan Li 12,  Anthony R Green 13,  Florian H Heidel 14,  Itay Tirosh 3,  Heike L Pahl 15,  Nils Leimkühler 16,  Natalie Köhler 1,  Marcelo A S de Toledo 10,  Steffen Koschmieder 17,  Robert Zeiser 1
Affiliations

Affiliations

  • 1 University of Freiburg Medical Center, Freiburg, Germany.
  • 2 Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 3 Weizmann Institute of Science, Rehovot, Israel.
  • 4 Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 5 University Medical Center Freiburg, Freiburg, Germany.
  • 6 Albert-Ludwigs-University, Freiburg, Germany.
  • 7 University of Minnesota, Minneapolis, MN, United States.
  • 8 Freiburg University Hospital, Freiburg, Germany.
  • 9 University of Freiburg, Freiburg, Germany.
  • 10 RWTH Aachen University, Aachen, Germany.
  • 11 Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 12 Cambridge Institute for Medical Research, Cambridge, United Kingdom.
  • 13 Cambridge Stem Cell Institute, Cambridge, United Kingdom.
  • 14 Hannover Medical School, Hannover, Germany.
  • 15 Department of Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany, Freiburg, Germany.
  • 16 Essen University Hospital, Essen, Germany.
  • 17 RWTH Aachen University, Aachen, NRW, Germany.
PMID: 38885318 DOI: 10.1158/0008-5472.CAN-23-3553
Abstract

Increasing evidence supports the interplay between oncogenic mutations and immune escape mechanisms. Strategies to counteract the immune escape mediated by oncogenic signaling could provide improved therapeutic options for patients with various malignancies. As mutant calreticulin (CALR) is a common driver of myeloproliferative neoplasms (MPN), we analyzed the impact of oncogenic CALRdel52 on the bone marrow (BM) microenvironment in MPN. Single-cell RNA-sequencing revealed that CALRdel52 led to the expansion of TGF-β1-producing erythroid progenitor cells and promoted the expansion of FoxP3+ regulatory T cells (Treg) in a murine MPN model. Treatment with an anti-TGF-β antibody improved mouse survival and increased the glycolytic activity in CD4+ and CD8+ T cells in vivo, while T cell depletion abrogated the protective effects conferred by neutralizing TGF-β. TGF-β1 reduced perforin and TNF-α production by T cells in vitro. TGF-β1 production by CALRdel52 cells was dependent on JAK1/2, PI3K, and ERK activity, which activated the transcription factor Sp1 to induce TGF-β1 expression. In four independent patient cohorts, TGF-β1 expression was increased in the BM of MPN patients compared to healthy individuals, and the BM of MPN patients contained a higher frequency of Treg compared to healthy individuals. Together, this study identified an ERK/Sp1/TGF-β1 axis in CALRdel52 MPNs as a mechanism of immunosuppression that can be targeted to elicit T-cell-mediated cytotoxicity.

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