Systemic Antitumor Immunity by PD-1/PD-L1 Inhibition Is Potentiated by Vascular-Targeted Photodynamic Therapy of Primary Tumors.
Systemic Antitumor Immunity by PD-1/PD-L1 Inhibition Is Potentiated by Vascular-Targeted Photodynamic Therapy of Primary Tumors.
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DOI：
10.1158/1078-0432.ccr-17-0186
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发表时间：
2018-02-01
期刊：
影响因子：
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通讯作者：
Coleman JA
中科院分区：
文献类型：
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作者：
O'Shaughnessy MJ;Murray KS;La Rosa SP;Budhu S;Merghoub T;Somma A;Monette S;Kim K;Corradi RB;Scherz A;Coleman JA
PD-1/PD-L1通路抑制对晚期肾细胞癌有效，尽管结果是可变的，可能取决于宿主因素，包括肿瘤微环境。使用光敏剂WST 11的血管靶向光动力（VTP）疗法诱导了明确的局部免疫应答，我们试图确定这是否可以增强对PD-1通路抑制的局部和全身抗肿瘤应答。使用发生肺转移的肾细胞癌原位Renca小鼠模型，我们用单独的VTP、单独的PD-1/PD-L1拮抗性抗体或VTP和抗体的组合治疗原发性肾肿瘤，然后检查治疗反应，包括原发性和转移部位的免疫浸润。还评估了人异种移植肿瘤中VTP对PD-L1表达的调节。在临床前小鼠模型中，用VTP联合全身性PD-1/PD-L1通路抑制治疗肾肿瘤，但单独治疗均未导致原发性肿瘤消退，阻止肺转移瘤生长并延长生存期。对肿瘤浸润淋巴细胞的分析显示，治疗效果与原发性肾肿瘤中CD 8+：调节性T细胞和CD 4 + FoxP 3 −：调节性T细胞比率增加以及肺转移部位T细胞浸润增加相关。此外，在人肾细胞癌异种移植物的VTP处理后诱导PD-L1表达。我们的研究结果证明了VTP与PD-1/PD-L1通路抑制相结合的局部免疫调节作用，可产生有效的局部和全身抗肿瘤反应。这种联合模式策略可能是对PD-1/PD-L1通路抑制单独耐药的癌症的有效疗法。
PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed. Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3−:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.