Effective combinatorial immunotherapy for penile squamous cell carcinoma

Tianhe Huang, Xi Cheng, Jad Chahoud, Ahmed Sarhan, Pheroze Tamboli, Priya Rao, Ming Guo, Ganiraju Manyam, Li Zhang, Yu Xiang, Leng Han, Xiaoying Shang, Pingna Deng, Yanting Luo, Xuemin Lu, Shan Feng, Magaly Martinez Ferrer, Y. Alan Wang, Ronald A. DePinho, Curtis A. Pettaway and Xin Lu ()
Additional contact information
Tianhe Huang: University of Notre Dame
Xi Cheng: University of Notre Dame
Jad Chahoud: The University of Texas MD Anderson Cancer Center
Ahmed Sarhan: The University of Texas MD Anderson Cancer Center
Pheroze Tamboli: The University of Texas MD Anderson Cancer Center
Priya Rao: The University of Texas MD Anderson Cancer Center
Ming Guo: The University of Texas MD Anderson Cancer Center
Ganiraju Manyam: The University of Texas MD Anderson Cancer Center
Li Zhang: University of Cincinnati
Yu Xiang: The University of Texas Health Science Center at Houston McGovern Medical School
Leng Han: The University of Texas Health Science Center at Houston McGovern Medical School
Xiaoying Shang: The University of Texas MD Anderson Cancer Center
Pingna Deng: The University of Texas MD Anderson Cancer Center
Yanting Luo: University of Notre Dame
Xuemin Lu: University of Notre Dame
Shan Feng: School of Life Sciences, Westlake University, Hangzhou
Magaly Martinez Ferrer: School of Pharmacy, University of Puerto Rico
Y. Alan Wang: The University of Texas MD Anderson Cancer Center
Ronald A. DePinho: The University of Texas MD Anderson Cancer Center
Curtis A. Pettaway: The University of Texas MD Anderson Cancer Center
Xin Lu: University of Notre Dame

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15980-9

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