TY - JOUR
T1 - Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
AU - Jayaprakash, Priyamvada
AU - Ai, Midan
AU - Liu, Arthur
AU - Budhani, Pratha
AU - Bartkowiak, Todd
AU - Sheng, Jie
AU - Ager, Casey
AU - Nicholas, Courtney
AU - Jaiswal, Ashvin R.
AU - Sun, Yanqiu
AU - Shah, Krishna
AU - Balasubramanyam, Sadhana
AU - Li, Nan
AU - Wang, Guocan
AU - Ning, Jing
AU - Zal, Anna
AU - Zal, Tomasz
AU - Curran, Michael A.
N1 - Funding Information:
MAC was supported in this work by a Cancer Research Institute CLIP Grant and by the MD Anderson Prostate Cancer SPORE (P50 CA140388) Career Development Program. These studies are currently being supported by an Individual Investigator Research Award from the Cancer Prevention and Research Institute of Texas (CPRIT RP170399). The MD Anderson Immunology Imaging Core and Flow Cytometry Core facilities assisted in these studies and are supported by the S10 RR029552 (NIH) and MD Anderson instrumentation grants. Threshold Inc. kindly provided TH-302 for this work as well as consultation on its use.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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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U2 - 10.1172/JCI96268
DO - 10.1172/JCI96268
M3 - Article
C2 - 30188869
AN - SCOPUS:85055773754
SN - 0021-9738
VL - 128
SP - 5137
EP - 5149
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -