Journal Article

CD4+ T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy

Guo, Junyi, Cao, Guoshuai, Tang, Jianfang, Xiao, Minglu, Ye, Jianqiang, Yao, Wei, Wen, Shuqiong, Wang, Zhiming, Luo, Yuan, Chen, Cheng, Xu, Lifan, Ye, Lilin, He, Ran, Wu, Qing, Chen, Xiangyu, Wang, Lisha, Xie, Luoyingzi, Lei, Shun, Huang, Qizhao, Wei, Zhengping, Huang, Jun, Yang, Xingxing, Wang, Pengcheng, Fang, Jingyi, Zhang, Yanyan

2022

Overview

BackgroundAntitumor 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 (TH1) 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 TH1 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 TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.MethodsListeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-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.ResultsCD4+ T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 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.ConclusionCD4+ T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Animals / Antibodies / Antigens / B7-H1 Antigen - pharmacology / Cancer / CD4-Positive T-Lymphocytes / CD8-Positive T-Lymphocytes / Clinical/Translational Cancer Immunotherapy / Cloning / Colorectal Neoplasms / Cytokines / Epitopes, T-Lymphocyte / Gene expression / Glycoproteins / Humans / Immune Checkpoint Inhibitors / Immunization / Immunotherapy / Influenza / Listeria / Lymphocytes / Melanoma / Metastasis / Mice / Ovalbumin / Pathogens / Programmed Cell Death 1 Receptor / Receptors, Antigen, T-Cell / T cell receptors / Tumor Microenvironment / Tumors / Vaccination / Vaccines / Viruses