A human mucosal melanoma organoid platform for modeling tumor heterogeneity and exploring immunotherapy combination options

• DOI: 10.1126/sciadv.adg6686
• Publication Date: 2023-10-27T18:02:44Z
• Authors: Lulu Sun; Xindan Kang; Houyu Ju; Chong Wang; Guizhu Yang; Rui Wang; Shuyang Sun
• Keywords: Organoid

Mucosal melanoma (MM), an aggressive rare subtype of melanoma, is distinct from cutaneous and has poor prognoses. We addressed the lack cell models for MM by establishing 30 organoids human oral (OMM), which retained major histopathological functional features parental tumors. Organoid groups derived chronologically or intratumorally lesions within same individual displayed heterogeneous genetics, expression profiles, drug responses, indicating rapid tumor evolution clinical response. Furthermore, transcriptome analysis revealed receptor tyrosine kinases (RTKs) signaling, particularly NGFR, a nerve growth factor receptor, was significantly up-regulated in OMMs patients resistant to anti-programmed death protein 1 (anti-PD-1) therapy. Combining anti-PD-1 with anlotinib (a phase 2 multitarget RTK inhibitor OMM) NGFR knockdown enhanced effective activity immune cells organoid-immune coculture systems. Together, our study suggested that OMM serve as faithful exploring immunotherapy combination strategies.