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; Xin Lu

doi:10.1038/s41467-020-15980-9

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. PettawayXin Lu

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49 Scopus citations

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.

Original language	English (US)
Article number	2124
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15980-9
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Huang, 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., ... Lu, X. (2020). Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nature communications, 11(1), Article 2124. https://doi.org/10.1038/s41467-020-15980-9

Huang, 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, MM, Alan Wang, Y, DePinho, RA , Pettaway, CA & Lu, X 2020, 'Effective combinatorial immunotherapy for penile squamous cell carcinoma', Nature communications, vol. 11, no. 1, 2124. https://doi.org/10.1038/s41467-020-15980-9

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title = "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.",

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

note = "Funding Information: We thank the members of our laboratories for helpful discussions. The research reported in this publication was supported by Award Grant Number# CA096297/CA096300 from the National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. X.L. was partially supported from Grant Numbers KL2 TR002530 and UL1 TR002529 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, Susan G. Komen Grant # CCR18548293, Boler Family Foundation endowment at University of Notre Dame. T.H. was partly supported by a graduate fellowship from China Scholarship Council. J.C. is supported by an ASCO Conquer Cancer Foundation Young Investigator Award. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

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doi = "10.1038/s41467-020-15980-9",

language = "English (US)",

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T1 - Effective combinatorial immunotherapy for penile squamous cell carcinoma

AU - Huang, Tianhe

AU - Cheng, Xi

AU - Chahoud, Jad

AU - Sarhan, Ahmed

AU - Tamboli, Pheroze

AU - Rao, Priya

AU - Guo, Ming

AU - Manyam, Ganiraju

AU - Zhang, Li

AU - Xiang, Yu

AU - Han, Leng

AU - Shang, Xiaoying

AU - Deng, Pingna

AU - Luo, Yanting

AU - Lu, Xuemin

AU - Feng, Shan

AU - Ferrer, Magaly Martinez

AU - Alan Wang, Y.

AU - DePinho, Ronald A.

AU - Pettaway, Curtis A.

AU - Lu, Xin

N1 - Funding Information: We thank the members of our laboratories for helpful discussions. The research reported in this publication was supported by Award Grant Number# CA096297/CA096300 from the National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. X.L. was partially supported from Grant Numbers KL2 TR002530 and UL1 TR002529 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, Susan G. Komen Grant # CCR18548293, Boler Family Foundation endowment at University of Notre Dame. T.H. was partly supported by a graduate fellowship from China Scholarship Council. J.C. is supported by an ASCO Conquer Cancer Foundation Young Investigator Award. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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ER -

Effective combinatorial immunotherapy for penile squamous cell carcinoma

Abstract

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MD Anderson CCSG core facilities

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