Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
复制标题
DOI：
10.1172/jci96268
复制
发表时间：
2018-11-01
影响因子：
15.9
通讯作者：
Curran, Michael A.
中科院分区：
文献类型：
--
作者：
Jayaprakash, Priyamvada;Ai, Midan;Curran, Michael A.
尽管针对黑色素瘤的免疫检查点阻断取得了成功，但许多“冷”肿瘤，如前列腺癌，仍然没有反应。我们发现，缺氧区在临床前前列腺癌中普遍存在，即使在CTLA-4和PD-1被阻断的情况下，也能抵抗T细胞的渗透。我们证明了低氧激活的前体药物TH-302减少或消除了这些肿瘤中的低氧。在转基因小鼠前列腺癌TRAMP-C2模型中，这种低氧前药和检查点阻断的联合治疗有效地治愈了80%以上的肿瘤。免疫荧光成像显示，TH-302促使T细胞涌入缺氧区，而缺氧区通过检查点封锁而扩大。此外，联合治疗将髓系来源的抑制细胞密度降低了50%以上，并持久地降低了肿瘤补充粒细胞亚群的能力。在完全抵抗检查点封锁的TraMP转基因小鼠中，36周龄的自发性前列腺癌肿瘤负担最小，联合治疗没有神经内分泌肿瘤的证据。Pten(PC-/-)Smad4(PC-/-)Ph-Cre4，Pten(PC-/-)Smad4(PC-/-)小鼠在低氧前药和检查点阻断的联合作用下，也显著延长了侵袭性前列腺癌的存活时间。缺氧的破坏和T细胞检查点的阻断可能会使一些最具治疗耐药性的癌症对免疫疗法敏感。
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, Pten(pc-/-) Smad4(pc-/-) 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.