CD4<sup>+</sup> T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy
Minglu Xiao, Luoyingzi Xie, Guoshuai Cao, Shun� Lei, Pengcheng Wang, Zhengping Wei, Yuan Luo, Jingyi Fang, Xingxing Yang, Qizhao Huang, Lifan Xu, Junyi Guo, Shuqiong Wen, Zhiming Wang, Qing Wu, Jianfang Tang, Lisha Wang, Xiangyu Chen, Cheng Chen, Yanyan Zhang, Wei Yao, Jianqiang Ye, Ran He, Jun Huang, Lilin Ye
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 (T H 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 T H 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 T H 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 (GP 61–80 ) or ovalbumin-specific CD4 + T cell epitope (OVA 323-339 ) 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 T H 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 T H 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.