Host Immunity Following Near-Infrared Photoimmunotherapy Is Enhanced with PD-1 Checkpoint Blockade to Eradicate Established Antigenic Tumors.
Host Immunity Following Near-Infrared Photoimmunotherapy Is Enhanced with PD-1 Checkpoint Blockade to Eradicate Established Antigenic Tumors.
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DOI：
10.1158/2326-6066.cir-18-0546
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发表时间：
2019-03
影响因子：
10.1
通讯作者：
Kobayashi H
中科院分区：
文献类型：
--
作者：
Nagaya T;Friedman J;Maruoka Y;Ogata F;Okuyama S;Clavijo PE;Choyke PL;Allen C;Kobayashi H
近红外光免疫疗法（NIR-PIT）可诱导免疫原性细胞死亡，但在同基因肿瘤小鼠模型中大多未能诱导持久的抗肿瘤反应。我们假设适应性免疫抵抗可能会限制 NIR-PIT 治疗后的持久反应。我们研究了在多个同基因肿瘤模型中结合 NIR-PIT 靶向细胞表面 CD44 和 PD-1 阻断的效果。在三个模型中的两个中，NIR-PIT 单一疗法阻止了肿瘤生长，增强了树突状细胞肿瘤浸润，并诱导了基线时不存在的从头肿瘤抗原特异性 T 细胞应答。添加 PD-1 阻断逆转了适应性免疫抵抗，从而增强了预先存在的肿瘤抗原特异性 T 细胞反应，并增强了 NIR-PIT 诱导的从头 T 细胞反应。增强的免疫反应与共有的肿瘤抗原表达相关，表明抗原性是 NIR-PIT 和 PD-1 联合阻断反应的主要决定因素。联合治疗诱导用 NIR-PIT 治疗的 MC38 肿瘤以及未经治疗的远处肿瘤的完全排斥。因此，在治疗和未治疗的肿瘤中测量了肿瘤抗原特异性 T 细胞反应，验证了全身抗肿瘤免疫的发展。清除肿瘤的小鼠抵抗了随后的肿瘤攻击，表明系统免疫记忆的存在。总的来说，这些结果表明，通过 NIR-PIT 诱导先天性和适应性免疫后，适应性免疫抵抗发生逆转，从而导致癌症抗原同基因模型中的高肿瘤排斥率和/或显着的肿瘤生长控制。
Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death, but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced de novo tumor antigen-specific T-cell responses absent at baseline. The addition of PD-1 blockade reversed adaptive immune resistance, resulting in both enhanced pre-existing tumor antigen-specific T-cell responses and enhanced de novo T-cell responses induced by NIR-PIT. Enhanced immune responses correlated with shared tumor antigen expression, suggesting that antigenicity is a major determinant of response to combination NIR-PIT and PD-1 blockade. Combination treatment induced complete rejection of MC38 tumors treated with NIR-PIT, as well as untreated, distant tumors. Accordingly, tumor antigen-specific T-cell responses were measured in both treated and untreated tumors, validating the development of systemic antitumor immunity. Mice that cleared tumors resisted subsequent tumor challenge, indicating the presence of systemic immune memory. Cumulatively these results demonstrate reversal of adaptive immune resistance following induction of innate and adaptive immunity by NIR-PIT, resulting in high rates of tumor rejection and/or significant tumor growth control in antigenic syngeneic models of cancer.