Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
| Autor: | Pratha Budhani, Midan Ai, Arthur Liu, Yanqiu Sun, Anna Zal, Guocan Wang, Nan Li, Krishna Shah, Jing Ning, Tomasz Zal, Todd Bartkowiak, Courtney Nicholas, Michael A. Curran, Jie Sheng, Sadhana Balasubramanyam, Ashvin R. Jaiswal, Casey R. Ager, Priyamvada Jayaprakash |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Combination therapy T-Lymphocytes medicine.medical_treatment T cell Adenocarcinoma Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine Cell Line Tumor medicine Animals Humans Hypoxia Mice Knockout business.industry Melanoma Prostatic Neoplasms Neoplasms Experimental General Medicine Immunotherapy biochemical phenomena metabolism and nutrition medicine.disease Cell Hypoxia Immune checkpoint Neoplasm Proteins Blockade Oxygen 030104 developmental biology medicine.anatomical_structure Nitroimidazoles 030220 oncology & carcinogenesis Commentary Cancer research bacteria Phosphoramide Mustards business Research Article |
| Zdroj: | Journal of Clinical Investigation. 128:5137-5149 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci96268 |
| Popis: | Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy. |
| Databáze: | OpenAIRE |
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