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Updated: Jul 10, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
β-Glucan-conjugated anti-PD-L1 antibody enhances antitumor efficacy in preclinical mouse models
Qian Wang1, Hao Jiang2, Hongli Zhang1
1Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Abstract:
The use of immune checkpoint blockade (ICB) is a promising approach for clinical cancer treatment. However, most of cancer patients do not respond to anti-PD-1/PD-L1 antibody. In this study, we proposed a novel strategy of antibody-β-glucan conjugates (AGC) to enhance the antitumor immune response to ICB therapy. The AGC were constructed by conjugating an anti-PD-L1 antibody with a β-glucan via click chemistry. This design facilitates the delivery of β-glucan into the tumor microenvironment (TME). Furthermore, the bridging effect mediated by AGC can promote the interaction between tumor cells and dendritic cells (DCs), thereby enhancing immunotherapeutic benefits. In the MC38 tumor-bearing mouse model, AGC demonstrated powerful tumor suppression, achieving a tumor suppression rate of 86.7 %. Immunophenotyping, cytokine analysis, RNA sequencing, and FTY720-treated models were combined to elucidate the mechanism underlying AGC function. Compared with anti-PD-L1 antibody, AGC induced an earlier immune response, infiltration of DCs, and activation of preexisting T cells in the TME, with T cells predominantly proliferating locally rather than migrating from other organs. In conclusion, these data suggest that AGC could serve as a promising strategy to improve ICB therapy with prospects for clinical utilization.
Insights
Antibody-β-glucan conjugates (AGC) enhance cancer immunotherapy by improving anti-PD-L1 antibody effectiveness. This novel approach boosts antitumor immune responses, offering a promising strategy for clinical cancer treatment.
Area of Science:
- Immunology
- Oncology
- Bioconjugation Chemistry
Background:
- Immune checkpoint blockade (ICB) shows promise in cancer treatment but faces limited patient response to anti-PD-1/PD-L1 antibodies.
- Developing strategies to enhance ICB efficacy is crucial for improving patient outcomes.
Purpose of the Study:
- To develop and evaluate novel antibody-β-glucan conjugates (AGC) for enhanced antitumor immune response in cancer therapy.
- To investigate the mechanism of action of AGC in the tumor microenvironment (TME).
Main Methods:
- Antibody-β-glucan conjugates (AGC) were synthesized by linking anti-PD-L1 antibodies with β-glucan using click chemistry.
- The efficacy of AGC was assessed in a MC38 tumor-bearing mouse model.
- Mechanisms were elucidated using immunophenotyping, cytokine analysis, RNA sequencing, and FTY720-treated models.
Main Results:
- AGC demonstrated significant tumor suppression (86.7%) in the MC38 model.
- Compared to anti-PD-L1 antibody alone, AGC induced an earlier immune response and enhanced dendritic cell (DC) infiltration in the TME.
- AGC promoted the activation and local proliferation of T cells within the TME.
Conclusions:
- Antibody-β-glucan conjugates (AGC) represent a promising strategy to potentiate anti-PD-L1 antibody therapy for cancer.
- AGC facilitate targeted delivery of β-glucan to the TME, promoting DC-tumor cell interaction and enhancing T cell-mediated antitumor immunity.
- The findings suggest AGC's potential for clinical application in improving ICB therapy.
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