. We have shown that regulatory T cells (Tregs) defeat anti-cancer immunity and that their depletion can be therapeutic, but their rapid regeneration is problematic. This project uses our discoveries that B7-H1 immune co-signaling facilitates Treg generation and that estrogen receptor (ER)? signals inhibit Treg regeneration in relevant pre-clinical mouse models with proven substantial translational relevance. Initial studies focus on ovarian cancer (OC) and use melanoma models to demonstrate concepts in additional tumors, as our discoveries should be applicable to a wide variety of cancers. Effects of B7-H1 on ER? signaling and relations to immune pathology and clinical outcomes are studied. Our overarching objective is to identify novel and effective immune therapy for cancers, with a focus on OC. Our overarching hypothesis is that B7-H1 blockade will augment Treg depletion as cancer immunotherapy and that ER? signals will boost B7-H1 blockade effects. This hypothesis predicts novel approaches to immunotherapy for OC, greatly extends our understanding of its immunopathogenesis and allows development of a similar strategy for other cancers and in men. ER? agonists can be used in males as we have shown and avoid estrogen side effects.
The specific aims are Aim 1 Test the hypothesis that ER? signals augment B7-H1 blockade effects in cancer and AIM 2 Test the hypothesis that dysfunctional B7-H1 signaling in cancer is dendritic cell-dependent.
These aims are achieved using mice genetically null for signaling components, pharmacologic agents affecting key signaling pathways, and bone marrow chimeras to study hematopoietic versus non-hematopoietic B7-H1 signals. Relevance. We seek to improve treatment options for OC, which kills over 15,000 American women annually, and for which there is no curative option after first-line therapy fails, as it doe in most cases. Principles can be applied to a wide variety of cancers, including melanoma, studied here as a confirmatory second cancer. Our insights into tumor-associated immune dysfunction promise to help improve the efficacy of cancer immunotherapy, whose record of success to date has been only modest.

Public Health Relevance

This project identifies means to improve the clinical and immune effectiveness of immune co-signaling blockade with anti-B7-H1 antibodies, using regulatory T cell depletion and estrogen receptor-? agonists in preclinical models for ovarian cancer (ID8 tumor) and melanoma (B16 tumor). The immunopathologic basis of B7-H1 signals in ovarian cancer and melanoma will be defined as well.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
Zip Code
Liu, Jinyou; Viswanadhapalli, Suryavathi; Garcia, Lauren et al. (2017) Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer. Oncotarget 8:50002-50014
Perales-Puchalt, Alfredo; Svoronos, Nikolaos; Rutkowski, Melanie R et al. (2017) Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 23:441-453
Zhang, Xiaowen; Chiang, Huai-Chin; Wang, Yao et al. (2017) Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nat Commun 8:15908
Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Allegrezza, Michael J et al. (2017) Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 7:72-85
Liu, Yang; Pandeswara, Srilakshmi; Dao, Vinh et al. (2017) Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment. Cancer Res 77:520-531
Gupta, Harshita B; Clark, Curtis A; Yuan, Bin et al. (2016) Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 1:
Clark, Curtis A; Gupta, Harshita B; Sareddy, Gangadhara et al. (2016) Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. Cancer Res 76:6964-6974
Dao, Vinh; Pandeswara, Srilakshmi; Liu, Yang et al. (2015) Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage. Cancer Prev Res (Phila) 8:400-9
Drerup, Justin M; Liu, Yang; Padron, Alvaro S et al. (2015) Immunotherapy for ovarian cancer. Curr Treat Options Oncol 16:317
Yuan, Bin; Cheng, Long; Chiang, Huai-Chin et al. (2014) A phosphotyrosine switch determines the antitumor activity of ER?. J Clin Invest 124:3378-90