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

• Published in: Nature communications Vol. 15; no. 1; pp. 9106 - 15
• Main Authors: Koya, Junji, Tanigawa, Tomohiko, Mizuno, Kota, Kim, Haryoon, Ito, Yuta, Yuasa, Mitsuhiro, Yamaguchi, Kentaro, Kogure, Yasunori, Saito, Yuki, Shingaki, Sumito, Tabata, Mariko, Murakami, Koichi, Chiba, Kenichi, Okada, Ai, Shiraishi, Yuichi, Marouf, Amira, Liévin, Raphaël, Chaubard, Sammara, Jaccard, Arnaud, Hermine, Olivier, de Leval, Laurence, Tournilhac, Olivier, Damaj, Gandhi, Gaulard, Philippe, Couronné, Lucile, Yasui, Teruhito, Nakashima, Kazutaka, Miyoshi, Hiroaki, Ohshima, Koichi, Kataoka, Keisuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/23; 38/91; 45; 631/250/580/1884; 631/67/1990/291/1621; Animals; Cell Line, Tumor; Chemokine CXCL16 - genetics; Chemokine CXCL16 - metabolism; Clonal deletion; CXCL16 protein; Disease Models, Animal; Epstein-Barr virus; Exocrine glands; Gene expression; Gene Expression Regulation, Neoplastic; Genetic engineering; Hematopoietic system; Herpesvirus 4, Human; Humanities and Social Sciences; Humans; Interferon-gamma - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; KLRG1 protein; Latency; Latent membrane protein 1; Lymphocytes T; Lymphoma; Lymphoma, Extranodal NK-T-Cell - genetics; Lymphoma, Extranodal NK-T-Cell - metabolism; Lymphoma, Extranodal NK-T-Cell - pathology; Lymphoma, Extranodal NK-T-Cell - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Myc protein; Myeloid cells; Myeloid Cells - metabolism; Neoplasia; Pathogenesis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, CXCR6 - genetics; Receptors, CXCR6 - metabolism; Salivary gland; Salivary glands; Salivary Glands - metabolism; Salivary Glands - pathology; Science; Science (multidisciplinary); Signal Transduction; T-cell lymphoma; Therapeutic targets; Tumor cells; Tumor Microenvironment - immunology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53376-1

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. Extranodal NK/T-cell lymphoma (ENKTCL) is an aggressive Epstein-Barr virus (EBV)-related neoplasm. Here the authors report a genetically engineered mouse model harboring NK-cellspecific Trp53 deletion to model ENKTCL in mice