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Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFβ Expression and Regulatory T-cell Expansion in the

Dominik Schmidt1,2, Cornelia Endres1,2, Rouven Hoefflin3

  • 1Department of Medicine I - Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Cancer Research
|June 17, 2024
PubMed

Insights

Targeting the mutant calreticulin (CALR) and TGFβ1 pathway in myeloproliferative neoplasms (MPN) enhances T-cell activity. This approach combats immune escape and offers new therapeutic strategies for MPN patients.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Oncogenic mutations, such as mutant calreticulin (CALR), drive myeloproliferative neoplasms (MPN).
  • Immune escape mechanisms are closely linked to oncogenic signaling, impacting cancer progression.
  • Targeting these pathways could yield novel therapeutic options for malignancies.

Purpose of the Study:

  • To investigate the impact of oncogenic CALRdel52 on the bone marrow microenvironment in MPN.
  • To elucidate the role of TGFβ1 in CALR-mutant MPN-associated immunosuppression.
  • To identify potential therapeutic targets for enhancing anti-tumor immunity in MPN.

Main Methods:

  • Single-cell RNA sequencing in a murine MPN model.
  • In vivo treatment with anti-TGFβ antibodies and T-cell depletion.
  • In vitro analysis of T-cell function under TGFβ1 influence.
  • Analysis of TGFβ1 signaling pathway components (JAK1/2, PI3K, ERK, Sp1).
  • Examination of patient cohorts for TGFβ1 expression and Treg frequency.

Main Results:

  • CALRdel52 induced expansion of TGFβ1-producing erythroid progenitors and regulatory T cells (Treg) in mice.
  • Anti-TGFβ antibody treatment improved survival and enhanced T-cell glycolytic activity in vivo.
  • TGFβ1 suppressed T-cell effector functions (perforin, TNFα production).
  • The ERK/Sp1 axis was identified as a key regulator of TGFβ1 production in CALR-mutant cells.
  • Elevated TGFβ1 and Treg frequencies were observed in the bone marrow of MPN patients.

Conclusions:

  • The study identified an ERK/Sp1/TGFβ1 signaling axis as a critical mechanism of immune suppression in CALRdel52-mutant MPN.
  • Targeting this axis can restore T-cell activity and cytotoxicity.
  • TGFβ antagonists represent a promising immunotherapeutic strategy for MPN treatment.

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