高干扰素敏感型流感病毒诱导适应性免疫反应并克服小鼠非小细胞肺癌中的抗PD-1抗药性

Hyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti-PD-1 in Murine Non-Small Cell Lung Cancer

Cancer Immunology Research

影响因子:8.2

分区:医学1区 Top / 免疫学2区肿瘤学2区

发表日期:2024 Dec 03

作者: Yushen Du, Ramin Salehi-Rad, Tian-Hao Zhang, William P Crosson, Jensen Abascal, Dongdong Chen, Yuan Shi, Hong Jiang, Yen-Wen Tseng, Xi Ma, Mengying Hong, Sihan Wang, Xijuan Wang, Kejun Tang, Shiyao Hu, Yuting Li, Shaokai Ni, Yiqi Cai, Shahed Tappuni, Yong Shen, Bin Liu, Ren Sun

DOI: 10.1158/2326-6066.CIR-23-1075

摘要

尽管免疫检查点抑制剂的免疫治疗取得了最新进展，但许多非小细胞肺癌（NSCLC）患者未能产生反应或在初期反应后出现耐药。原位疫苗（ISV）利用工程病毒已成为一种有前景的抗原非依赖策略，既能调节肿瘤微环境，又能增强抗肿瘤T细胞反应，从而克服免疫耐药。我们通过全基因组功能筛选，构建了高干扰素敏感性（HIS）病毒，向流感病毒基因组引入了八个IFN敏感突变。与野生型流感病毒相比，HIS在免疫完整的宿主中复制受抑制，显示出作为癌症治疗的安全性。HIS ISV在小鼠NSCLC模型中引发强烈而短暂的I型干扰素反应，导致多功能效应性Th1 CD4+ T细胞和细胞毒性CD8+ T细胞在肿瘤中富集。与野生型病毒相比，HIS在多种具有不同驱动突变和突变负荷的同源鼠模型中表现出增强的抗肿瘤效果。这一效果依赖于宿主的I型干扰素反应和T淋巴细胞。HIS成功克服了LKB1缺失的小鼠NSCLC对抗PD-1的耐药，显著改善了总体生存率及系统性肿瘤特异性免疫。这些研究提供了有力证据，支持将HIS作为一种“现成”的ISV策略，进一步临床评估用于对免疫检查点抑制剂耐药的NSCLC患者。

Abstract

Despite recent advances in immunotherapy with immune checkpoint inhibitors, many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment and augment antitumor T-cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, hyper-IFN-sensitive (HIS) virus, by conducting a genome-wide functional screening and introducing eight IFN-sensitive mutations in the influenza genome to enhance host IFN response. Compared with wild-type influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4+ T cells and cytotoxic CD8+ T cells into the tumor. HIS ISV demonstrated enhanced antitumor efficacy compared with wild-type in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti-PD-1 in LKB1-deficient murine NSCLC, resulting in improved overall survival and systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as an "off-the-shelf" ISV strategy for patients with NSCLC refractory to immune checkpoint inhibitors.