Huang, TianheCheng, XiChahoud, JadSarhan, AhmedTamboli, PherozeRao, PriyaGuo, MingManyam, GanirajuZhang, LiXiang, YuHan, LengShang, XiaoyingDeng, PingnaLuo, YantingLu, XueminFeng, ShanFerrer, Magaly MartinezWang, Y. AlanDePinho, Ronald A.Pettaway, Curtis A.Lu, Xin2020-07-222020-07-222020-05-01Huang, T., Cheng, X., Chahoud, J., Sarhan, A., Tamboli, P., Rao, P., Guo, M., Manyam, G., Zhang, L., Xiang, Y., Han, L., Shang, X., Deng, P., Luo, Y., Lu, X., Feng, S., Ferrer, M. M., Alan Wang, Y., DePinho, R. A., Pettaway, C. A., … Lu, X. (2020). Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nature communications, 11(1), 2124. https://doi.org/10.1038/s41467-020-15980-9https://hdl.handle.net/1805/23339Penile 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.en-USAttribution 4.0 InternationalCancer microenvironmentCancer modelsTumour immunologyTumour-suppressor proteinsPenile cancerArticle