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

Abstract

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.

The role of CD4+ T cells in tumor and chronic viral immune responses

“…Moreover, MHC‐II epitopes can shape antitumor immunity and synergize with immunotherapy 400,401 . In our study, we found that the MHC‐II‐restricted epitope‐based heterologous prime‐boost vaccination potentiates antitumor immunity and PD‐1/PD‐L1 immunotherapy 402 . Besides, a heterologous prime‐boost immunization based on MHC‐II‐restricted epitope selectively induces virus‐specific CD4 + T cell responses and control chronic viral infection 403 .…”

PD-1 blockade potentiates neoadjuvant chemotherapy in NSCLC via increasing CD127+ and KLRG1+ CD8 T cells

“…Although anti-PD1 antibodies primarily target T cells, B and CD4 + T cells were essential in ICB-driven anti-tumor responses via secreting antibody and helping T cell response, as indicated by depletion of B cells significantly reduced therapeutic response to anti-PD1 in mice model 52 . CD4 + T cells can profoundly modulate the TME by secreting different types of cytokines 53 or by directly eliminating cancer cells 54 . Cui et al 20 demonstrated that neoantigen-driven B cells promoted CD4 + T follicular helper cells to secret IL-21 to boost anti-tumor CD8 + T cell responses in a murine model of lung adenocarcinoma.…”

Prognostic Value of Liver Kinase B1 (LKB1) in Gastric Cancer-Associated Tumor Microenvironment Immunity

“…However, studies have indicated that dysfunction of CTL in infiltration leads to immune evasion and ultimately failure to attack cancer cells [ 37 ]. PD−1/PD−L1 blockade was demonstrated to eliminate established tumors via dysfunctional CTL reinvigorating anti−tumor immunity [ 38 ]. We showed that PD−1/PD−L1 was highly expressed in LKB1 high expressing subgroups of GC patients, suggesting that LKB1 might be associated with T−cell immune checkpoints.…”