Xiao, Xie, Cao, and Lei et al. showed that prophylactic and therapeutic i.p. or s.c. prime-boost heterologous vaccine strategies using exogenous or endogenous tumor-associated CD4+ T cell epitopes reduced tumor growth (which required CD4+ and CD8+ T cells), metastases, and post-resection recurrence, and enabled recall responses in mouse models. Vaccination induced CD4+ TILs that were TH1-polarized, promoted polyclonal expansion and effector function of tumor-specific CD8+ TILs, synergized with anti-PD-L1, and sustained antitumor effects by preventing tumor-specific CD8+ T cell re-exhaustion after stopping anti-PD-L1 treatment.
Contributed by Paula Hochman
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.
Author Info: (1) Institute of Immunology, Third Military Medical University, Chongqing, China. Department of Dermatology, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
Author Info: (1) Institute of Immunology, Third Military Medical University, Chongqing, China. Department of Dermatology, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Institute of Immunology, Third Military Medical University, Chongqing, China. (3) Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, USA. (4) Institute of Immunology, Third Military Medical University, Chongqing, China. Department of Aviation Physiology Training, Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, China. (5) Key Laboratory of Nephrology, Jinling Hospital National Clinical Research Center of Kidney Diseases, Nanjing, Jiangsu, China. (6) Institute of Immunology, Third Military Medical University, Chongqing, China. (7) Department of Immunology, Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine, Wuhan, Hubei, China. (8) Institute of Immunology, Third Military Medical University, Chongqing, China. (9) Institute of Cancer, Third Military Medical University Second Affiliated Hospital, Chongqing, China. (10) School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China. (11) Institute of Immunology, Third Military Medical University, Chongqing, China. (12) Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. (13) Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. (14) Institute of Immunology, Third Military Medical University, Chongqing, China. (15) Institute of Immunology, Third Military Medical University, Chongqing, China. (16) Institute of Immunology, Third Military Medical University, Chongqing, China. (17) Institute of Immunology, Third Military Medical University, Chongqing, China. (18) School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China. (19) Institute of Immunology, Third Military Medical University, Chongqing, China. (20) Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China. (21) Institute of Immunology, Third Military Medical University, Chongqing, China. (22) Key Laboratory of Jiangsu Preventive Veterinary Medicine, Key Laboratory for Avian Preventive Medicine, Ministry of Education, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China yelilinlcmv@163.com huangjun@uchicago.edu ranhe@hust.edu.cn jqye@yzu.edu.cn. (23) Department of Immunology, Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine, Wuhan, Hubei, China yelilinlcmv@163.com huangjun@uchicago.edu ranhe@hust.edu.cn jqye@yzu.edu.cn. (24) Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, USA yelilinlcmv@163.com huangjun@uchicago.edu ranhe@hust.edu.cn jqye@yzu.edu.cn. (25) Institute of Immunology, Third Military Medical University, Chongqing, China yelilinlcmv@163.com huangjun@uchicago.edu ranhe@hust.edu.cn jqye@yzu.edu.cn.
