Effective combinatorial immunotherapy for penile squamous cell carcinoma.

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.

• Authors: 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, Xin Lu
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2124 (05 01 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32358507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• SOXB1 Transcription Factors
• Sox2 protein, mouse
• Cisplatin

Topics

• Animals
• Carcinoma, Squamous Cell (metabolism, therapy)
• Cell Line
• Cisplatin (pharmacology)
• Humans
• Immunohistochemistry
• Immunotherapy (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (drug effects, metabolism)
• Myeloid-Derived Suppressor Cells (cytology, metabolism)
• Penile Neoplasms (metabolism, therapy)
• Proteomics
• SOXB1 Transcription Factors (genetics, metabolism)
• Tissue Array Analysis
• Transcriptome (genetics)