2. Academic Validation
  3. MHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides

MHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides

  • Nat Commun. 2024 Jan 25;15(1):752. doi: 10.1038/s41467-024-45083-8.
Yun-Tsan Chang 1,  Pacôme Prompsy 1,  Susanne Kimeswenger 2,  Yi-Chien Tsai 1,  Desislava Ignatova 3,  Olesya Pavlova 1,  Christoph Iselin 1,  Lars E French 4 5,  Mitchell P Levesque 3,  François Kuonen 1,  Malgorzata Bobrowicz 6,  Patrick M Brunner 7,  Steve Pascolo 3,  Wolfram Hoetzenecker 8,  Emmanuella Guenova 9 10 11
Affiliations

Affiliations

  • 1 Department of Dermatology, Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • 2 Department of Dermatology and Venerology, Medical Faculty, Johannes Kepler University, Linz, Austria.
  • 3 Department of Dermatology, University Hospital of Zurich and Faculty of Medicine, University of Zurich, Zurich, Switzerland.
  • 4 Department of Dermatology and Allergology, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 5 Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
  • 7 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, USA.
  • 8 Department of Dermatology and Venerology, Medical Faculty, Johannes Kepler University, Linz, Austria. wolfram.hoetzenecker@kepleruniklinikum.at.
  • 9 Department of Dermatology, Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. emmanuella.guenova@unil.ch.
  • 10 Department of Dermatology, University Hospital of Zurich and Faculty of Medicine, University of Zurich, Zurich, Switzerland. emmanuella.guenova@unil.ch.
  • 11 Department of Dermatology, Hospital 12 de Octubre, Medical School, University Complutense, Madrid, Spain. emmanuella.guenova@unil.ch.
PMID: 38272918 DOI: 10.1038/s41467-024-45083-8
Abstract

Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of Antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32β-major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients' skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.

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