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http://ir.nhri.org.tw/handle/3990099045/15078
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| Title: | A novel combination therapy of arginine deiminase and an arginase inhibitor targeting arginine metabolism in the tumor and immune microenvironment |
| Authors: | Ye, PH;Li, CY;Cheng, HY;Anuraga, G;Wang, CY;Chen, FW;Yang, SJ;Lee, KT;Chang, KY;Lai, MD |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Tumor progression is dependent on tumor cells and their microenvironment. It is important to identify therapies that inhibit cancer cells and activate immune cells. Arginine modulation plays a dual role in cancer ther-apy. Arginase inhibition induced an anti-tumor effect via T-cell activation through an increase in arginine in the tumor environment. In contrast, arginine depletion by arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG 20) induced an anti-tumor response in argininosuccinate synthase 1 (ASS1)-deficient tumor cells. ADI-PEG 20 did not cause toxicity to normal immune cells, which can recycle the ADI-degraded prod-uct citrulline back to arginine. To target tumor cells and their neighboring immune cells, we hypothesized that the combination of an arginase inhibitor (L-Norvaline) and ADI-PEG 20 may trigger a stronger anticancer response. In this study, we found that L-Norvaline inhibits tumor growth in vivo. Pathway analysis based on RNA-seq data indicated that the differentially expressed genes (DEGs) were significantly enriched in some immune-related path-ways. Significantly, L-Norvaline did not inhibit tumor growth in immunodeficient mice. In addition, combination treat-ment with L-Norvaline and ADI-PEG 20 induced a more robust anti-tumor response against B16F10 melanoma. Furthermore, single-cell RNA-seq data demonstrated that the combination therapy increased tumor-infiltrating CD8+ T cells and CCR7+ dendritic cells. The increase in infiltrated dendritic cells may enhance the anti-tumor response of CD8+ cytotoxic T cells, indicating a potential mechanism for the observed anti-tumor effect of the combination treat-ment. In addition, populations of immunosuppressive-like immune cells, such as S100a8+ S100a9+ monocytes and Retnla+ Retnlg+ TAMs, in tumors were dramatically decreased. Importantly, mechanistic analysis indicated that the processes of the cell cycle, ribonucleoprotein complex biogenesis, and ribosome biogenesis were upregulated after combination treatment. This study implied the possibility of L-Norvaline as a modulator of the immune response in cancer and provided a new potential therapy combined with ADI-PEG 20. |
| Date: | 2023-05-30 |
| Relation: | American Journal of Cancer Research. 2023 May 30;13(5):1952-1969. |
| Link to: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244097/ |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2156-6976&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:001002130900019 |
| Appears in Collections: | [張光裕] 期刊論文
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| ISI001002130900019.pdf | | 9512Kb | Adobe PDF | 134 | View/Open |
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