Song, Lu, and Shi et al. demonstrated that an MHC-II restricted neoantigen vaccine (M44) increased inflammatory signaling within the TME, enhanced CD4+ and CD8+ T cell infiltration, and reduced tumor growth in B16 tumors, while showing signs of T cell exhaustion. Vaccination increased the inferred interaction between TIGIT on T cells and its ligand PVR on myeloid cells, impairing the function and proliferation of Th1 and effector and memory CD8+ T cells. M44 vaccine plus TIGIT antibody inhibited tumor growth, enhanced the helper and cytotoxic functions of antigen-specific CD4+ T cells, and increased effector and memory CD8+ T cells.
Contributed by Shishir Pant
Background: Cold tumors, characterized by poor T cell infiltration and an immunosuppressive tumor microenvironment (TME), are generally resistant to immune-checkpoint inhibitors (ICIs). Although CD4+ T cells play a critical role in anti-tumor immunity, it remains unclear whether major histocompatibility complex (MHC)-II-restricted neoantigen vaccines can reprogram the immunosuppressive TME and overcome ICI resistance.
Methods: Using the B16F10 model, we evaluated the MHC-II-restricted vaccine efficacy, profiled immune responses via flow cytometry and single-cell RNA sequencing, and identified the potential combination therapy targets poliovirus receptor (PVR) via NicheNet analysis. The combined efficacy was then validated in vitro and in vivo.
Findings: MHC-II-restricted neoantigen vaccine promoted inflammatory signaling within the TME and enhanced infiltration of CD4+ and CD8+ T cells, along with increased interferon (IFN)-γ production and signs of T cell exhaustion, which provided a prerequisite for ICI response. NicheNet analysis revealed enrichment of the inhibitory immune-checkpoint axis PVR-T cell immunoglobulin and ITIM domain (TIGIT) following vaccination. The combination of the vaccines and TIGIT blockade exhibited synergistic anti-tumor efficacy. This combination enhanced cytokine production by antigen-specific T cells, promoted effector memory differentiation, and delayed exhaustion of CD8+ T cells.
Conclusions: MHC-II-restricted neoantigen vaccine remodels the immune inhibitory TME with insufficient T cell infiltration and synergizes with TIGIT blockade to suppress tumor growth, providing a promising combinatorial strategy for cold tumors.
Funding: Supported by the National Key Research and Development Program of China (2023YFC2506400), the National Natural Science Foundation (82373263), and the Fundamental Research Funds for the Central Universities (0214-14380506).
Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) MOE Key Laboratory of Model Animal fo
Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China. (3) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (4) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (5) MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China. (6) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (7) Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China. (8) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (9) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (10) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (11) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (12) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China; Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi 214101, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China. Electronic address: yanli@nju.edu.cn. (13) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China; Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: jiawei99@nju.edu.cn.
