Effective combinatorial immunotherapy for penile squamous cell carcinoma.
Tianhe HuangXi ChengJad ChahoudAhmed SarhanPheroze TamboliPriya RaoMing GuoGaniraju C ManyamLi ZhangYu XiangLeng HanXiaoying ShangPingna DengYanting LuoXuemin LuShan FengMagaly Martinez FerrerY Alan WangRonald A DePinhoCurtis A PettawayXin LuPublished in: Nature communications (2020)
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.
Keyphrases
- squamous cell carcinoma
- cancer therapy
- mouse model
- epithelial mesenchymal transition
- transforming growth factor
- induced apoptosis
- case control
- radical prostatectomy
- cell cycle arrest
- lymph node metastasis
- mass spectrometry
- locally advanced
- stem cells
- pi k akt
- high throughput
- cell proliferation
- drug delivery
- cardiovascular events
- signaling pathway
- type diabetes
- endoplasmic reticulum stress
- mesenchymal stem cells
- cell death
- oxidative stress
- rectal cancer
- human health
- single cell
- metastatic renal cell carcinoma