Nature communications · 2020
Effective combinatorial immunotherapy for penile squamous cell carcinoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Huang Tianhe, Cheng Xi, Chahoud Jad, Sarhan Ahmed, Tamboli Pheroze, Rao Priya, Guo Ming, Manyam Ganiraju, Zhang Li, Xiang Yu, Han Leng, Shang Xiaoying, Deng Pingna, Luo Yanting, Lu Xuemin, Feng Shan, Ferrer Magaly Martinez, Alan Wang Y, DePinho Ronald A, Pettaway Curtis A, Lu Xin
Аннотация
Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.