The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy
文献类型：期刊论文
| 作者 | Zhang, Ying3,12,13; Akhil, Venu12,13; Seo, Ho Seong11; Park, Hae Ran11,13; Kim, Soo Hyun8,9,10; You, Sung-Hwan7,12,13; Liu, Zhipeng6; Kim, So -young7,12,13; Sultonova, Rukhsora D.4,5,12,13; Min, Jung-Joon1,7,12,13 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2024 |
| 卷号 | 14期号:3页码:1195-1211 |
| 关键词 | Cancer radiotherapy immunogenic cell death calreticulin L-ASNase reactive oxygen species immune checkpoint inhibitor |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.90376 |
| 通讯作者 | Min, Jung-Joon(jjmin@jnu.ac.kr) ; Hong, Yeongjin(yjhong@jnu.ac.kr) |
| 英文摘要 | Radiotherapy (RT) triggers immunogenic cell death (ICD). L-ASNase, which catalyzes the conversion of asparagine (Asn), thereby depleting it, is used in the treatment of blood cancers. In previous work, we showed that CRT3LP and CRT4LP, PASylated L-ASNases conjugated to the calreticulin (CRT) -specific monobodies CRT3 and CRT4, increase the efficacy of ICD-inducing chemotherapy. Here, we assessed their efficacy in tumor -bearing mice treated with RT. Methods: Monobody binding was evaluated by in silico molecular docking analysis. The expression and cellular localization of ecto-CRT were assessed by confocal imaging and flow cytometry. The antitumor effect and the roles of CRT3LP and CRT4LP in irradiation (IR)-induced ICD in tumors were analyzed by ELISA, immunohistochemistry, and immune analysis methods. Results: Molecular docking analysis showed that CRT3 and CRT4 monobodies were stably bound to CRT. Exposure to 10 Gy IR decreased the viability of CT -26 and MC -38 tumor cells in a time -dependent manner until 72 h, and increased the expression of the ICD marker ecto-CRT (CRT exposed on the cell surface) and the immune checkpoint marker PD -L1 until 48 h. IR enhanced the cytotoxicity of CRT3LP and CRT4LP in CT -26 and MC -38 tumor cells, and increased reactive oxygen species (ROS) levels. In mice bearing CT -26 and MC -38 subcutaneous tumors treated with 6 Gy IR, Rluc8-conjugated CRT -specific monobodies (CRT3-Rluc8 and CRT4-Rluc8) specifically targeted tumor tissues, and CRT3LP and CRT4LP increased total ROS levels in tumor tissues, thereby enhancing the antitumor efficacy of RT. Tumor tissues from these mice showed increased mature dendritic, CD4+ T, and CD8+ T cells and pro -inflammatory cytokines (IFN gamma and TNF alpha) and decreased regulatory T cells, and the expression of tumor cell proliferation markers (Ki67 and CD31) was downregulated. These data indicate that the combination of IR and CRT -targeting L-ASNases activated and reprogramed the immune system of the tumor microenvironment. Consistent with these data, an immune checkpoint inhibitor (anti -PD -L1 antibody) markedly increased the therapeutic efficacy of combined IR and CRT -targeting L-ASNases. Conclusion: CRT -specific L-ASNases are useful as additive drug candidates in tumors treated with RT, and combination treatment with anti -PD -L1 antibody increases their therapeutic efficacy. |
| WOS关键词 | SUPEROXIDE-DISMUTASE SOD2 ; L-ASPARAGINASE ; CANCER ; APOPTOSIS ; CELLS ; SYNTHETASE |
| 资助项目 | Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) - Korean government (MSIT)[NRF-2020M3A9G 3080330] ; Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) - Korean government (MSIT)[NRF-2020M3A9G3080282] ; NRF - MSIT[2020R1A5A2031185] ; Postdoctoral Fellowship Program of CPSF[GZC20232842] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001163065500010 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/310118]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Min, Jung-Joon; Hong, Yeongjin |
| 作者单位 | 1.Chonnam Natl Univ, Med Sch, Dept Nucl Med, 264 Seoyang Ro, Hwasun Eup 58128, Jeollanam Do, South Korea 2.Chonnam Natl Univ, Med Sch, Dept Surg, 264 Seoyang Ro, Hwasun Eup 58128, Hwasun, South Korea 3.Chinese Acad Sci, Shanghai Inst Mat Med, Mol Imaging Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Republican Oncol Res Ctr, Tashkent Reg Branch, Tashkent, Uzbekistan 5.New Uzbekistan Univ, Tashkent, Uzbekistan 6.Chonnam Natl Univ, Hwasun Hosp, Biomed Res Inst, Brain Tumor Res Lab, Gwangju 58128, South Korea 7.CNCure Biotech Inc, Dept Biol Sci, Daegu, Jeonranam Do, South Korea 8.Chonnam Natl Univ Hosp, Gwangju, South Korea 9.Chonnam Natl Univ, Dept Lab Med, Med Sch, Gwangju, Hwasun, South Korea 10.Chonnam Natl Univ, Dept Microbiol, Med Sch, Gwangju, Jeollanam Do, South Korea |
| 推荐引用方式 GB/T 7714 | Zhang, Ying,Akhil, Venu,Seo, Ho Seong,et al. The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy[J]. THERANOSTICS,2024,14(3):1195-1211. |
| APA | Zhang, Ying.,Akhil, Venu.,Seo, Ho Seong.,Park, Hae Ran.,Kim, Soo Hyun.,...&Hong, Yeongjin.(2024).The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy.THERANOSTICS,14(3),1195-1211. |
| MLA | Zhang, Ying,et al."The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy".THERANOSTICS 14.3(2024):1195-1211. |
入库方式： OAI收割
来源：上海药物研究所
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