Oncolytic poxvirus CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model
Oncolytic poxvirus CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model
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DOI：
10.1080/2162402x.2020.1729300
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Fong, Yuman
中科院分区：
文献类型：
--
作者：
Chaurasiya, Shyambabu;Yang, Annie;Fong, Yuman
三阴性乳腺癌是乳腺癌中最具侵袭性的亚型，且难以治疗。乳腺癌被认为免疫原性较差，因此对免疫疗法的反应较差。我们测试了溶瘤痘病毒CF33-hNIS-Delta F14.5是否可以调节肿瘤免疫微环境并使肿瘤对免疫检查点抑制剂抗PD-L1产生反应。我们发现，病毒感染导致体外和小鼠体内三阴性乳腺癌细胞的 PD-L1 水平上调。在原位三阴性乳腺癌小鼠模型中，发现该病毒会增加 CD8+ T 细胞的肿瘤浸润。同样，在用 CF33-hNIS-Delta F14.5 治疗的小鼠中，在肿瘤中发现了高水平的促炎细胞因子 IFN γ 和 IL-6，但在血清中没有发现。在接受病毒和抗 PD-L1 抗体联合治疗的小鼠中，免疫调节水平甚至更高。虽然 CF33-hNIS-Delta F14.5 和抗 PD-L1 抗体作为单一药物未能发挥显着的抗肿瘤作用，但两种药物的组合产生了显着的抗肿瘤效果，当两种药物注射到肿瘤内时，50% 的小鼠经历了肿瘤完全消退。此外，“治愈”的小鼠在用相同的癌细胞重新攻击后没有出现肿瘤，这表明它们对这些癌细胞产生了免疫力。综上所述，我们的研究表明，CF33-hNIS-Delta F14.5 在三阴性乳腺癌模型中有利地调节肿瘤免疫微环境，使其对免疫检查点抑制剂抗 PD-L1 产生反应，因此需要进一步研究以确定这种联合疗法的临床适用性。
Triple-negative breast cancer is the most aggressive subtype of breast cancer and is difficult to treat. Breast cancer is considered to be poorly immunogenic and hence is less responsive to immunotherapies. We tested whether the oncolytic poxvirus CF33-hNIS-Delta F14.5 could modulate tumor immune microenvironment and make the tumors responsive to the immune checkpoint inhibitor anti-PD-L1. We found that virus infection causes the upregulation of PD-L1 levels on triple-negative breast cancer cells in vitro as well as in vivo in mice. In a mouse model of orthotopic triple-negative breast cancer, the virus was found to increase tumor infiltration by CD8+ T cells. Likewise, in mice treated with CF33-hNIS-Delta F14.5 high levels of proinflammatory cytokines IFN gamma and IL-6 were found in the tumors but not in the serum. The levels of immune modulation were even higher in mice that were treated with a combination of the virus and anti-PD-L1 antibody. While CF33-hNIS-Delta F14.5 and anti-PD-L1 antibody failed to exert significant anti-tumor effect as a single agent, a combination of the two agents resulted in significant anti-tumor effect with 50% mice experiencing complete tumor regression when both agents were injected intra-tumorally. Furthermore, the 'cured' mice did not develop tumor after re-challenge with the same cancer cells suggesting that they developed immunity against those cancer cells. Taken together, our study shows that CF33-hNIS-Delta F14.5 favorably modulates tumor immune microenvironment in triple-negative breast cancer model making them responsive to the immune checkpoint inhibitor anti-PD-L1, and hence warrants further studies to determine the clinical applicability of this combination therapy.