Metformin reduces PD-L1 on tumor cells and enhances the anti-tumor immune response generated by vaccine immunotherapy

• Type of Material: Article
• Authors: Luis Enrique Munoz, Emory University; Lei Huang, Emory University; Ramireddy Bommireddy, Emory University; Richa Sharma, Emory University; Lenore Monterroza, Emory University; Rohini N. Guin, Emory University; Sarah G. Samaranayake, Emory University; Christopher D. Pack, Metaclipse Therapeutics Corp; Sampath Ramachandiran, Metaclipse Therapeutics Corp; Shaker J. C. Reddy, Metaclipse Therapeutics Corp; Malathy Shanmugam, Emory University; Periasamy Selvaraj, Emory University
• Language: English
• Date: 2021-11-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2022
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2021-002614
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 9
• Issue: 11
• Grant/Funding Information: This work was supported by NCI/NIH R01 grants R01 CA202763 to PS and CDP, and R01CA208328to MS, and a Diversity Supplement R01 CA202763-S to LEM.
• Keywords: immunologic; vaccine; Life Sciences & Biomedicine; THERAPY; immunogenicity; INHIBITION; PROLIFERATION; vaccination; T-CELLS; PATHWAY; DELIVERY; programmed cell death 1 receptor; Immunology; EXPRESSION; adjuvants; immunotherapy; PROTEIN TRANSFER; Science & Technology; Oncology; MAPK
• Research Categories: Biology, Virology; Biology, Cell; Health Sciences, Immunology

Abstract

Background PD-L1 is one of the major immune checkpoints which limits the effectiveness of antitumor immunity. Blockade of PD-L1/PD-1 has been a major improvement in the treatment of certain cancers, however, the response rate to checkpoint blockade remains low suggesting a need for new therapies. Metformin has emerged as a potential new drug for the treatment of cancer due to its effects on PD-L1 expression, T cell responses, and the immunosuppressive environment within tumors. While the benefits of metformin in combination with checkpoint blockade have been reported in animal models, little remains known about its effect on other types of immunotherapy. Methods Vaccine immunotherapy and metformin were administered to mice inoculated with tumors to investigate the effect of metformin and TMV vaccine on tumor growth, metastasis, PD-L1 expression, immune cell infiltration, and CD8 T cell phenotype. The effect of metformin on IFN-γinduced PD-L1 expression in tumor cells was assessed by flow cytometry, western blot, and RT-qPCR. Results We observed that tumors that respond to metformin and vaccine immunotherapy combination show a reduction in surface PD-L1 expression compared with tumor models that do not respond to metformin. In vitro assays showed that the effect of metformin on tumor cell PD-L1 expression was mediated in part by AMP-activated protein kinase signaling. Vaccination results in increased T cell infiltration in all tumor models, and this was not further enhanced by metformin. However, we observed an increased number of CD8 T cells expressing PD-1, Ki-67, Tim-3, and CD62L as well as increased effector cytokine production after treatment with metformin and tumor membrane vesicle vaccine. Conclusions Our data suggest that metformin can synergize with vaccine immunotherapy to augment the antitumor response through tumor-intrinsic mechanisms and also alter the phenotype and function of CD8 T cells within the tumor, which could provide insights for its use in the clinic.