TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity.
TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity.
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DOI：
10.1158/0008-5472.can-14-3511
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发表时间：
2015-06-01
期刊：
影响因子：
11.2
通讯作者：
Demaria S
中科院分区：
文献类型：
--
作者：
Vanpouille-Box C;Diamond JM;Pilones KA;Zavadil J;Babb JS;Formenti SC;Barcellos-Hoff MH;Demaria S
针对内源性肿瘤抗原的 T 细胞是肿瘤消退的强大介质。最近的免疫疗法进展已经确定了有效的干预措施，可以在自然产生肿瘤的患者中释放肿瘤特异性 T 细胞活性。引发针对患者个体肿瘤的 T 细胞反应仍然是一个重大挑战。放射治疗可以诱导针对肿瘤表达的模型抗原的免疫反应，但目前尚不清楚它是否可以有效地启动对免疫原性较差的肿瘤表达的内源性抗原具有特异性的 T 细胞。我们假设 TGFβ 活性是阻碍辐射产生原位肿瘤疫苗能力的主要障碍。在这里，我们表明，在免疫原性较差的小鼠癌症中，放射治疗过程中抗体介导的 TGFβ 中和有效地产生了针对多种内源性肿瘤抗原的 CD8+ T 细胞反应。生成的 T 细胞可有效引起受辐射肿瘤和未受辐射肺转移瘤或同时性肿瘤的消退（远隔效应）。在联合放疗和 TGFβ 阻断治疗的肿瘤中检测到与 IFNγ 和免疫介导的排斥反应相关的基因特征，但未单独使用。肿瘤细胞和骨髓细胞中程序性死亡 (PD) 配体-1 和 -2 以及瘤内 T 细胞上 PD-1 的上调限制了肿瘤排斥，导致快速复发。添加抗 PD-1 抗体可延长放射和 TGFβ 阻断所实现的生存期。因此，TGFβ是放射治疗产生原位肿瘤疫苗能力的基本调节剂。局部放射治疗与 TGFβ 中和相结合，为患者提供了一种新颖的个体化疫苗接种策略来对抗肿瘤。
T cells directed to endogenous tumor antigens are powerful mediators of tumor regression. Recent immunotherapy advances have identified effective interventions to unleash tumor-specific T cell activity in patients who naturally develop them. Eliciting T cell responses to a patient's individual tumor remains a major challenge. Radiation therapy can induce immune responses to model antigens expressed by tumors, but it remains unclear if it can effectively prime T cells specific for endogenous antigens expressed by poorly immunogenic tumors. We hypothesized that TGFβ activity is a major obstacle hindering the ability of radiation to generate an in situ tumor vaccine. Here we show that antibody-mediated TGFβ neutralization during radiation therapy effectively generates CD8+ T cell responses to multiple endogenous tumor antigens in poorly immunogenic mouse carcinomas. Generated T cells were effective at causing regression of irradiated tumors and non-irradiated lung metastases or synchronous tumors (abscopal effect). Gene signatures associated with IFNγ and immune-mediated rejection were detected in tumors treated with radiation therapy and TGFβ blockade in combination but not as single agents. Upregulation of programmed death (PD) ligand-1 and -2 in neoplastic and myeloid cells and PD-1 on intratumoral T cells limited tumor rejection resulting in rapid recurrence. Addition of anti-PD-1 antibodies extended survival achieved with radiation and TGFβ blockade. Thus, TGFβ is a fundamental regulator of radiation therapy ability to generate an in situ tumor vaccine. The combination of local radiation therapy with TGFβ neutralization offers a novel individualized strategy for vaccinating patients against their tumors.