Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers
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Background: Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn 2+) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods: The effect of Mn 2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn 2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn 2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results: Mn 2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn 2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn 2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn 2+ plus anti-PD-L1 therapy, Mn 2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn 2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn 2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion: Combining Mn 2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.
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α-PD-1/PD-L1 antibodies take advantage of STING agonist-induced PD-L1 upregulation.
“On the other hand, α-PD-1/PD-L1 antibodies take advantage of STING agonist-induced PD-L1 upregulation [273].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [273]
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- Authors
- Yi, M., Niu, M., Zhang, J., Li, S., Zhu, S., Yan, Y., Li, N., Zhou, P., Chu, Q., & Wu, K.
- Affiliations
- Tongji Hospital (CN)
- Wuhan YZY Biopharma (China) (CN)
- Zhengzhou University (CN)
- Corresponding author
- Wu, Kongming
- Venue
- Journal of Hematology & Oncology
- Published
- 2021-09-15
- Volume
- 14
- Issue
- 1
- Pages
- 146-146
- ISSN
- 1756-8722 (ISSN-L)
- PMC
- PMC8442312
- OpenAlex
- W3200648346
- Cited by
- 163
- References
- 67
- Citations by year
- 2026: 23 · 2025: 25 · 2024: 44 · 2023: 32 · 2022: 37 · 2021: 2
- FWCI
- 10.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Hematology & Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- national natural science foundation of china (82073370, 81874120)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- manganese, STING pathway, dendritic cell maturation, immune-excluded tumors, immunotherapy resistance, combination immunotherapy, tumor microenvironment, T cell activation, tumor-infiltrating lymphocytes, antitumor immunity, anti-PD-L1 resistance
- MeSH terms
- Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Animals, Drug Synergism, Humans, Immunotherapy, Manganese, Mice, Inbred BALB C, Neoplasms, Transforming Growth Factor beta, Antibodies, Bispecific, Cell Line, Tumor, Mice
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