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Published on: March 6, 2018
LGALS9 blockade augments vaccine-induced immune responses against prostate cancer
Bowen Lu1, Ning Liu2, Wanting Zhao1
1Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Background:
Prostate-specific membrane antigen (PSMA)-based vaccination represents a promising immunotherapeutic strategy for prostate cancer; however, its efficacy remains constrained by tumor-induced immune evasion and insufficient activation of antigen-presenting cells. Galectin-9 (LGALS9), an immunoregulatory lectin that contributes to immune suppression, is therefore an attractive target for overcoming tumor-induced immune tolerance.
Methods:
Recombinant adenoviral vaccines encoding PSMA and LGALS9 (Ad-PSMA and Ad-LGALS9) were generated and validated for antigen expression in vitro and in vivo. Therapeutic efficacy was evaluated in murine subcutaneous, bone metastatic, and humanized prostate cancer models. Vaccine-induced immune responses were characterized by flow cytometry, ELISA, enzyme-linked immunospot (ELISpot), immunohistochemistry, EdU proliferation assays, cytotoxic T lymphocyte assays, and cell depletion experiments.
Results:
Pre-immunization with Ad-LGALS9 significantly potentiated the therapeutic efficacy of the Ad-PSMA vaccine in subcutaneous, bone metastatic, and humanized prostate cancer models, resulting in pronounced tumor growth inhibition and prolonged survival. Mechanistically, LGALS9 targeting enhanced dendritic cell (DC) activation and maturation, upregulating CD80, CD86, major histocompatibility complex-II, and CD40 expression and promoting efficient antigen cross-presentation. This facilitated robust priming and expansion of multifunctional CD8+ T cells producing interferon-γ, interleukin-2, and tumor necrosis factor-α, which mediated potent cytotoxicity against PSMA-expressing tumor cells. Furthermore, LGALS9 immunization induced high-titer neutralizing antibodies that disrupted the LGALS9/TIM-3 inhibitory axis, alleviating T-cell exhaustion. Combined Ad-LGALS9/PSMA vaccination established durable memory CD8+ T-cell responses that conferred protection against tumor rechallenge.
Conclusions:
Targeting LGALS9 enhances DC-mediated CD8+ T-cell immunity and synergistically augments the therapeutic efficacy of tumor vaccines, representing a promising immunotherapeutic strategy for prostate cancer.
Insights
Targeting Galectin-9 (LGALS9) enhances prostate cancer vaccines by boosting immune cell activity. This approach improves tumor control and survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Prostate-specific membrane antigen (PSMA)-based vaccines show promise for prostate cancer immunotherapy.
- Tumor-induced immune evasion and poor antigen-presenting cell activation limit current vaccine efficacy.
- Galectin-9 (LGALS9) is an immunoregulatory lectin contributing to immune suppression and is a target for overcoming immune tolerance.
Purpose of the Study:
- To evaluate the therapeutic efficacy of combining PSMA-based vaccination with Galectin-9 (LGALS9) targeting.
- To investigate the underlying immunological mechanisms by which LGALS9 modulation enhances anti-tumor immunity.
Main Methods:
- Generated recombinant adenoviral vaccines encoding PSMA and LGALS9 (Ad-PSMA, Ad-LGALS9).
- Assessed therapeutic efficacy in murine subcutaneous, bone metastatic, and humanized prostate cancer models.
- Characterized immune responses using flow cytometry, ELISA, ELISpot, IHC, proliferation, CTL assays, and cell depletion.
Main Results:
- Pre-immunization with Ad-LGALS9 significantly enhanced Ad-PSMA vaccine efficacy, inhibiting tumor growth and prolonging survival.
- LGALS9 targeting improved dendritic cell activation and antigen cross-presentation, leading to robust CD8+ T cell priming.
- Vaccination induced neutralizing antibodies against LGALS9, alleviating T-cell exhaustion and establishing durable memory responses.
Conclusions:
- Targeting LGALS9 synergistically enhances PSMA-based vaccine efficacy by boosting DC-mediated CD8+ T cell immunity.
- This combined strategy represents a promising immunotherapeutic approach for prostate cancer.
- LGALS9 modulation is a viable method to overcome immune evasion in prostate cancer treatment.
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