Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets

Junji Koya, Tomohiko Tanigawa, Kota Mizuno, Haryoon Kim, Yuta Ito, Mitsuhiro Yuasa, Kentaro Yamaguchi, Yasunori Kogure, Yuki Saito, Sumito Shingaki, Mariko Tabata, Koichi Murakami, Kenichi Chiba, Ai Okada, Yuichi Shiraishi, Amira Marouf, Raphaël Liévin, Sammara Chaubard, Arnaud Jaccard, Olivier Hermine, Laurence Leval, Olivier Tournilhac, Gandhi Damaj, Philippe Gaulard, Lucile Couronné, Teruhito Yasui, Kazutaka Nakashima, Hiroaki Miyoshi, Koichi Ohshima and Keisuke Kataoka ()
Additional contact information
Junji Koya: National Cancer Center Research Institute
Tomohiko Tanigawa: National Cancer Center Research Institute
Kota Mizuno: National Cancer Center Research Institute
Haryoon Kim: National Cancer Center Research Institute
Yuta Ito: National Cancer Center Research Institute
Mitsuhiro Yuasa: National Cancer Center Research Institute
Kentaro Yamaguchi: National Cancer Center Research Institute
Yasunori Kogure: National Cancer Center Research Institute
Yuki Saito: National Cancer Center Research Institute
Sumito Shingaki: National Cancer Center Research Institute
Mariko Tabata: National Cancer Center Research Institute
Koichi Murakami: National Cancer Center Research Institute
Kenichi Chiba: National Cancer Center Research Institute
Ai Okada: National Cancer Center Research Institute
Yuichi Shiraishi: National Cancer Center Research Institute
Amira Marouf: Université Paris Cité
Raphaël Liévin: Université Paris Cité
Sammara Chaubard: Limoges University Hospital
Arnaud Jaccard: Limoges University Hospital
Olivier Hermine: Université Paris Cité
Laurence Leval: Lausanne University Hospital and Lausanne University
Olivier Tournilhac: Clermont Auvergne University
Gandhi Damaj: Normandy University
Philippe Gaulard: IMRB
Lucile Couronné: Université Paris Cité
Teruhito Yasui: National Institutes of Biomedical Innovation, Health and Nutrition
Kazutaka Nakashima: Kurume University
Hiroaki Miyoshi: Kurume University
Koichi Ohshima: Kurume University
Keisuke Kataoka: National Cancer Center Research Institute

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

Abstract: Abstract Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies.

Date: 2024
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DOI: 10.1038/s41467-024-53376-1

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