Immunology Department, Hospital Universitario de la Princesa. Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain.
B Lymphocyte Lab, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
J Immunother Cancer. 2020 Sep;8(2). doi: 10.1136/jitc-2020-001187.
Lung cancer is one of the most frequent malignancies in humans and is a major cause of death. A number of therapies aimed at reinforcing antitumor immune response, including antiprogrammed cell death protein 1 (anti-PD-1) antibodies, are successfully used to treat several neoplasias as non-small cell lung cancer (NSCLC). However, host immune mechanisms that participate in response to anti-PD-1 therapy are not completely understood.
We used a syngeneic immunocompetent mouse model of NSCLC to analyze host immune response to anti-PD-1 treatment in secondary lymphoid organs, peripheral blood and tumors, by flow cytometry, immunohistochemistry and quantitative real-time PCR (qRT-PCR). In addition, we also studied specific characteristics of selected immune subpopulations in ex vivo functional assays.
We show that anti-PD-1 therapy induces a population of circulating T follicular helper cells (cTfh) with enhanced B activation capacity, which participates in tumor response to treatment. Anti-PD-1 increases the number of tertiary lymphoid structures (TLS), which correlates with impaired tumor growth. Of note, TLS support cTfh-associated local antibody production, which participates in host immune response against tumor.
These findings unveil a novel mechanism of action for anti-PD-1 therapy and provide new targets for optimization of current therapies against lung cancer.
肺癌是人类最常见的恶性肿瘤之一，也是主要的死亡原因。许多旨在增强抗肿瘤免疫反应的疗法，包括抗程序性细胞死亡蛋白 1（抗 PD-1）抗体，已成功用于治疗包括非小细胞肺癌（NSCLC）在内的多种肿瘤。然而，参与抗 PD-1 治疗反应的宿主免疫机制尚不完全清楚。
我们使用 NSCLC 的同源免疫活性小鼠模型，通过流式细胞术、免疫组织化学和实时定量 PCR（qRT-PCR）分析宿主对抗 PD-1 治疗的次级淋巴器官、外周血和肿瘤中的免疫反应。此外，我们还在体外功能测定中研究了选定免疫亚群的特定特征。
我们表明，抗 PD-1 治疗诱导了一群具有增强 B 激活能力的循环滤泡辅助 T 细胞（cTfh），它们参与了肿瘤对治疗的反应。抗 PD-1 增加了三级淋巴结构（TLS）的数量，这与肿瘤生长受损有关。值得注意的是，TLS 支持 cTfh 相关的局部抗体产生，这参与了宿主对肿瘤的免疫反应。
这些发现揭示了抗 PD-1 治疗的一种新作用机制，并为优化当前针对肺癌的治疗方法提供了新的靶点。
