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Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
Open accessAbstract
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.
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“In mouse models, hypoxic zones within tumors were shown to lack T cells (37, 38).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [38]
In the citing paper
“High concentrations of oxygen activate the anticancer effects of T cells and NK cells by deactivating the adenosine immunosuppressive microenvironment. 127 , 206 , 408”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [127]
In the citing paper
“Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy13–19.”
In the citing paper
“there are also opposite reports showing that tumor hypoxia induces mouse T cell exhaustion and resistance to immunotherapy and depletion of HIF1α increases NK cell activity and tumor infiltration16,17,19,48,49.”
In the citing paper
“Current studies have focused on the role of hypoxia-induced metabolic reprogramming in causing T cell dysfunction and exhaustion16,19,52–55.”
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Metadata
- Authors
- Jayaprakash, P., Ai, M., Liu, A., Budhani, P., Bartkowiak, T., Sheng, J., Ager, C., Nicholas, C., Jaiswal, A. R., Sun, Y., Shah, K., Balasubramanyam, S., Li, N., Wang, G., Ning, J., Zal, A., Zal, T., & Curran, M. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Curran, Michael A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-10-15
- Volume
- 128
- Issue
- 11
- Pages
- 5137-5149
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6205399
- OpenAlex
- W2890762462
- Cited by
- 399
- References
- 42
- Citations by year
- 2026: 36 · 2025: 42 · 2024: 47 · 2023: 54 · 2022: 75 · 2021: 72 · 2020: 48 · 2019: 22 · 2018: 3
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Prevention Research Institute of Texas (RP170399)
- Cancer Research Institute (CLIP-Curran)
- National Cancer Institute (P50 CA140388)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Keywords
- prostate cancer, tumor hypoxia, TH-302, hypoxia-activated prodrug, CTLA-4 blockade, anti-PD-1 therapy, immune checkpoint blockade, T cell infiltration, cold tumors, myeloid-derived suppressor cells, immunotherapy resistance, PTEN, SMAD4, neuroendocrine prostate cancer
- MeSH terms
- Adenocarcinoma, Animals, Immunotherapy, Male, Neoplasm Proteins, Neoplasms, Experimental, Nitroimidazoles, Phosphoramide Mustards, Prostatic Neoplasms, T-Lymphocytes, Cell Hypoxia, Mice, Knockout, Cell Line, Tumor, Mice
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