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.
Authors
- Jensen Abascal (ORCID: https://orcid.org/0000-0002-7529-1004)
- Yushen Du (ORCID: https://orcid.org/0000-0002-8015-4207)
- Yuan Shi (ORCID: https://orcid.org/0000-0002-9993-0448)
- Shahed Tappuni
- Kejun Tang (ORCID: https://orcid.org/0000-0002-9461-3646)
- Xijuan Wang (ORCID: https://orcid.org/0000-0001-5908-9458)
- Tian-hao Zhang (ORCID: https://orcid.org/0000-0002-4422-5581)
- Shiyao Hu (ORCID: https://orcid.org/0000-0001-8043-9061)
- Ren Sun (ORCID: https://orcid.org/0000-0002-8628-7019)
- William P. Crosson (ORCID: https://orcid.org/0000-0003-1886-4301)
- Yiqi Cai
- Ramin Salehi‐Rad (ORCID: https://orcid.org/0000-0003-1543-5421)
- Sihan Wang (ORCID: https://orcid.org/0000-0002-9712-2105)
- Dongdong Chen
- Yuting Li (ORCID: https://orcid.org/0009-0008-5686-2140)
- Yen-Wen Tseng
- Mengying Hong (ORCID: https://orcid.org/0000-0003-0939-3616)
- Bin Liu (ORCID: https://orcid.org/0000-0001-8083-8062)
- Xi Ma (ORCID: https://orcid.org/0000-0003-1976-7351)
- Yong Shen (ORCID: https://orcid.org/0000-0002-1232-7970)
- Hong Jiang (ORCID: https://orcid.org/0000-0003-3652-6488)
- Shaokai Ni
Institutions
- University of California, Los Angeles (US)
- Westlake University (CN)
- Olive View-UCLA Medical Center (US)
- Ministry of Education (ET)
- VA Greater Los Angeles Healthcare System (US)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1158/2326-6066.cir-23-1075
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- U.S. Department of Veterans Affairs
- Biomedical Laboratory Research and Development, VA Office of Research and Development
- National Natural Science Foundation of China
- Zhejiang University
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- Jonsson Comprehensive Cancer Center