Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
Priyamvada Jayaprakash, … , Tomasz Zal, Michael A. Curran
Priyamvada Jayaprakash, … , Tomasz Zal, Michael A. Curran
Published September 6, 2018
Citation Information: J Clin Invest. 2018;128(11):5137-5149. https://doi.org/10.1172/JCI96268.
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Research Article Immunology Oncology

Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy

Abstract

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.

Authors

Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin R. Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, Michael A. Curran

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Figure 5

Hypoxia ablation and checkpoint blockade causes persistent defects in the capacity of prostate tumors to replenish their Gr-MDSCs.

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Hypoxia ablation and checkpoint blockade causes persistent defects in th...
(A) Large, established TRAMP-C2 tumors were treated with a single cycle of therapy, rested for 2 days, and then congenically marked bone marrow myeloid progenitor cells were adoptively transferred in order to assess the influence of prior therapy on their subsequent polarization within the tumor microenvironment. (B) TRAMP-C2 tumors preestablished 32 days earlier were treated with TH-302 and antibody or left untreated, and then immature bone marrow myeloid cells (CD11b+Lin–) from B6.SJL (CD45.1+) mice were injected via tail vein. After 60 hours, tumor-infiltrating myeloid cells were isolated and analyzed by flow cytometry. The frequency of tumor-infiltrating CD45.1+ myeloid cells polarized to Gr-MDSCs (CD11b+Ly6G+Ly6C–CD45.1+) is shown relative to untreated animals. (C) The phenotype of Gr-MDSCs (CD11b+Ly6G+Ly6C–CD45.1+) is shown for arginase and MHC II expression (MFI relative to untreated) (5–10 mice per group, n = 2). Statistical significance between groups was determined by ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.