CD4+ T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy. Issue 5 (17th May 2022)

• Record Type: Journal Article
• Authors: Xiao, Minglu; Xie, Luoyingzi; Cao, Guoshuai; Lei, Shun; Wang, Pengcheng; Wei, Zhengping; Luo, Yuan; Fang, Jingyi; Yang, Xingxing; Huang, Qizhao; Xu, Lifan; Guo, Junyi; Wen, Shuqiong; Wang, Zhiming; Wu, Qing; Tang, Jianfang; Wang, Lisha; Chen, Xiangyu; Chen, Cheng; Zhang, Yanyan; Yao, Wei; Ye, Jianqiang; He, Ran; Huang, Jun; Ye, Lilin
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 5(2022)
• Publication Date: 2022-05-17
• Subjects: Vaccination -- CD4-Positive T-Lymphocytes -- Immunotherapy -- CD8-Positive T-Lymphocytes -- Immunization; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-004022
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8 + T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8 + T-cell epitopes can drive the functional exhaustion of tumor-specific CD8 + T cells. Tumor-specific type-I helper CD4 + T (TH 1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8 + T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4 + T-cell epitopes to induce tumor-specific TH 1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH 1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy. Methods: Listeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-A b -restricted CD4 + T cell epitope (GP61–80 ) or ovalbumin-specific CD4 + T cell epitope (OVA323-339 ) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4 + T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing. Results: CD4 + T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH 1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8 + T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8 + T cells. Conclusion: CD4 + T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH 1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.