Journal Article

Effective combinatorial immunotherapy for penile squamous cell carcinoma

Han, Leng, Luo, Yanting, Pettaway, Curtis A., Chahoud, Jad, Alan Wang, Y., Tamboli, Pheroze, Zhang, Li, Deng, Pingna, Xiang, Yu, Huang, Tianhe, Manyam, Ganiraju, DePinho, Ronald A., Cheng, Xi, Ferrer, Magaly Martinez, Shang, Xiaoying, Sarhan, Ahmed, Feng, Shan, Rao, Priya, Lu, Xin, Lu, Xuemin, Guo, Ming

2020

Overview

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/Ap c 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. Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 13/89 / 14/19 / 38/39 / 38/91 / 49/79 / 631/67/1244 / 631/67/327 / 631/67/580 / 631/67/589/1721 / 631/67/70 / 64/60 / 96/47 / 96/98 / Adenomatous polyposis coli / Androgens / Animal models / Animals / Cancer / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - therapy / Celecoxib / Cell Line / Chemoresistance / Cisplatin / Cisplatin - pharmacology / Clinical trials / Combinatorial analysis / Deletion / Developing countries / Drug screening / Epithelium / Genetic engineering / Genital cancers / Humanities and Social Sciences / Humans / Immune checkpoint / Immunohistochemistry / Immunosuppressive agents / Immunotherapy / Immunotherapy - methods / Inhibitor drugs / LDCs / Male / Mice / Mice, Inbred C57BL / Molecular modelling / Morbidity / Mortality / multidisciplinary / Myeloid Cells - drug effects / Myeloid Cells - metabolism / Myeloid-Derived Suppressor Cells - cytology / Myeloid-Derived Suppressor Cells - metabolism / Penile Neoplasms - metabolism / Penile Neoplasms - therapy / Penis / Proteomics / PTEN protein / Science / Science (multidisciplinary) / Smad4 protein / SOXB1 Transcription Factors - genetics / SOXB1 Transcription Factors - metabolism / Squamous cell carcinoma / Suppressor cells / Tissue Array Analysis / Transcriptome - genetics