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

Yun-Tsan Chang, Pacôme Prompsy, Susanne Kimeswenger, Yi-Chien Tsai, Desislava Ignatova, Olesya Pavlova, Christoph Iselin, Lars E. French, Mitchell P. Levesque, François Kuonen, Malgorzata Bobrowicz, Patrick M. Brunner, Steve Pascolo, Wolfram Hoetzenecker () and Emmanuella Guenova ()
Additional contact information
Yun-Tsan Chang: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Pacôme Prompsy: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Susanne Kimeswenger: Medical Faculty, Johannes Kepler University
Yi-Chien Tsai: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Desislava Ignatova: University Hospital of Zurich and Faculty of Medicine, University of Zurich
Olesya Pavlova: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Christoph Iselin: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Lars E. French: Ludwig-Maximilians-University of Munich
Mitchell P. Levesque: University Hospital of Zurich and Faculty of Medicine, University of Zurich
François Kuonen: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne
Malgorzata Bobrowicz: Medical University of Warsaw
Patrick M. Brunner: Icahn School of Medicine at Mount Sinai
Steve Pascolo: University Hospital of Zurich and Faculty of Medicine, University of Zurich
Wolfram Hoetzenecker: Medical Faculty, Johannes Kepler University
Emmanuella Guenova: Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45083-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45083-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45083-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().