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2 results on '"Shuxiao Guan"'

1. Metabolic reprogramming by adenosine antagonism and implications in non-small cell lung cancer therapy

Author

Shuxiao Guan, Shankar Suman, Joseph M. Amann, Ruohan Wu, David P. Carbone, Jie Wang, and Mikhail M. Dikov

Subjects
Non-small cell lung cancer, Tumor and immune cells, Gene mutation, A2AR/A2BR antagonist, Tumor microenvironment, Metabolism, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Non-small cell lung cancer (NSCLC) is a heterogeneous disease with genetic and environmental parameters that influence cell metabolism. Because of the complex interplay of environmental factors within the tumor microenvironment (TME) and the profound impact of these factors on the metabolic activities of tumor and immune cells, there is an emerging interest to advance the understanding of these diverse metabolic phenotypes in the TME. High levels of adenosine are characteristic of the TME, and adenosine can have a significant impact on both tumor cell growth and the immune response. Consistent with this, we showed in NSCLC data from TCGA that high expression of the A2BR leads to worse outcome and that expression of A2BR may be different for different mutation backgrounds. We then investigated the metabolic reprogramming of tumor cells and immune cells (T and dendritic cells) by adenosine. We used A2AR and A2BR antagonism or agonism as well as receptor knockout animals to explore whether these treatments altered specific immune compartments or conferred specific therapeutic vulnerabilities. Using the seahorse assay, we found that an A2BR antagonist modulates oxidative stress homeostasis in NSCLC cell lines. In addition, we found distinct metabolic roles of A2AR and A2BR receptors in T cell activation and dendritic cell maturation. These data suggest potential mechanisms and therapeutic benefits of A2 receptor antagonist therapy in NSCLC.

Published
2022
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2. Improving combination therapies: Targeting A2B adenosine receptor to modulate metabolic tumor microenvironment and immunosuppression

Author

Jason V Evans, Shankar Suman, Mounika Uttam L Goruganthu, Elena E Tchekneva, Shuxiao Guan, Rajeswara Rao Arasada, Anneliese Antonucci, Longzhu Piao, Irina Ilgisonis, Andrey A Bobko, Benoit Driesschaert, Roman V Uzhachenko, Rebecca Hoyd, Alexandre Samouilov, Joseph Amann, Ruohan Wu, Lai Wei, Aaditya Pallerla, Sergey V Ryzhov, Igor Feoktistov, Kyungho P Park, Takefumi Kikuchi, Julio Castro, Alla V Ivanova, Thanigaivelan Kanagasabai, Dwight H Owen, Daniel J Spakowicz, Jay L Zweier, David P Carbone, Sergey V Novitskiy, Valery V Khramtsov, Anil Shanker, and Mikhail M Dikov

Subjects
Cancer Research, Oncology
Abstract

Background We investigated the role of A2B-adenosine receptor (A2BAR) in regulating immunosuppressive metabolic stress in the tumor microenvironment (TME). Novel A2BAR antagonist PBF-1129 was tested for anti-tumor activity in animals and evaluated for safety and immunological efficacy in a phase-I clinical trial in non-small-cell lung cancer (NSCLC) patients. Methods Anti-tumor efficacy of A2BAR antagonists and impact on metabolic and immune TME was evaluated in lung, melanoma, colon, breast and EGFR-inducible transgenic cancer models. Employing Electron Paramagnetic Resonance, we assessed changes in TME metabolic parameters including pO2, pH, and inorganic phosphate (Pi) during tumor growth and evaluated the immunological effects of PBF-1129, including its pharmacokinetics, safety, and toxicity in NSCLC patients. Results Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial Pi emerged as a correlative and cumulative measure of TME stress and immunosuppression. A2BAR inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ecto-nucleotidases, increased expression of adenosine deaminase (ADA), decreased tumor growth and metastasis, increased IFN-γ-production and enhanced the efficacy of anti-tumor therapies following combination regimens in animal models (anti-PD-1 vs. anti-PD-1 plus PBF-1129 treatment hazard ratio [HR] = 11.74, 95% CI = 3.35 to 41.13, n = 10, P Conclusions Data identify A2BAR as a valuable therapeutic target to modify metabolic and immune TME to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.

Published
2023
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