Abstract
Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exo- somes to reprogram the factors associated with the tumor microenvironment (TME) causing tu- mor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with re- ceptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some pa- tients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef- fect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Im- mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider- ation. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/ PD-L1 therapy resistance and increase the patient’s drug response rate.
Document Type
Article
Publication Date
2023
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.gendis.2023.01.026
Funding Information
The work was supported by the National Institutes of Health (No. R01 CA266579 to Zhiguo Li) and partially supported by the UK CARES Career Development Program (No. P30 ES026529) and the American Cancer Society (No. IRG 19-140- 31).
Repository Citation
Alam, Rakibul; Rahman, Mizanur; and Li, Zhiguo, "The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy" (2023). Markey Cancer Center Faculty Publications. 202.
https://uknowledge.uky.edu/markey_facpub/202
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Biochemistry Commons, Cell Biology Commons, Medical Genetics Commons, Molecular Biology Commons, Oncology Commons
Notes/Citation Information
© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).