超干扰素敏感性流感诱导适应性免疫反应,克服小鼠非小细胞肺癌对抗 PD-1 的耐药性。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
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
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引用次数: 0

摘要

尽管免疫检查点抑制剂(ICI)的免疫疗法取得了最新进展,但许多非小细胞肺癌(NSCLC)患者在初次应答后仍无反应或产生抗药性。使用工程病毒进行原位接种(ISV)已成为一种很有前景的抗原诊断策略,它既能调节肿瘤微环境(TME),又能增强抗肿瘤T细胞反应,从而克服免疫耐受。我们通过进行全基因组功能筛选并在流感基因组中引入八个干扰素(IFN)敏感突变,设计出了一种减毒活疫苗--高干扰素敏感病毒(HIS)。与野生型(WT)流感相比,HIS 在免疫功能健全的宿主体内的复制能力减弱,从而提高了其作为癌症治疗安全选择的潜力。HIS ISV能在小鼠NSCLCs中引起强健但短暂的I型IFN反应,导致肿瘤中富集多功能效应Th1 CD4和细胞毒性CD8 T细胞。与 WT 相比,HIS ISV 在多种具有不同驱动基因突变和不同突变负荷的 NSCLC 合成小鼠模型中显示出更强的抗肿瘤功效。这种疗效取决于宿主的 1 型 IFN 反应和 T 淋巴细胞。HIS ISV克服了LKB-1缺陷小鼠NSCLC对抗PD-1的耐药性,从而提高了总生存率和持久的全身肿瘤特异性免疫力。这些研究提供了令人信服的证据,支持进一步对 HIS 进行临床评估,将其作为 ICI 难治性 NSCLC 患者的一种新型 "现成 "ISV 策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti-PD-1 in Murine Non-Small Cell Lung Cancer.

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.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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