{"title":"抗血管内皮生长因子受体2-干扰素α通过上调CCL5的表达促进结直肠癌中CD8+T细胞的浸润","authors":"Linhua Huang, Rui Gao, Lidi Nan, Jingyao Qi, Siyu Yang, Shuai Shao, Jiajun Xie, Mingzhu Pan, Tianquan Qiu, Juan Zhang","doi":"10.1097/CJI.0000000000000516","DOIUrl":null,"url":null,"abstract":"SUMMARY\nImmunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Anti-VEGFR2-Interferon α Promotes the Infiltration of CD8+ T Cells in Colorectal Cancer by Upregulating the Expression of CCL5.\",\"authors\":\"Linhua Huang, Rui Gao, Lidi Nan, Jingyao Qi, Siyu Yang, Shuai Shao, Jiajun Xie, Mingzhu Pan, Tianquan Qiu, Juan Zhang\",\"doi\":\"10.1097/CJI.0000000000000516\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"SUMMARY\\nImmunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.\",\"PeriodicalId\":15996,\"journal\":{\"name\":\"Journal of Immunotherapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2024-04-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Immunotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/CJI.0000000000000516\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Immunotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/CJI.0000000000000516","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
摘要免疫细胞因子是一种很有前景的癌症免疫治疗方法。抗血管内皮生长因子受体2-干扰素α(IFNα)可抑制结直肠癌(CRC)的生长,并增强肿瘤微环境中 CD8+ T 细胞的浸润,具有巨大的临床转化潜力。然而,抗血管内皮生长因子受体2-IFNα如何招募T细胞的机制尚未阐明。在这里,我们证实了抗血管内皮生长因子受体2-IFNα抑制了癌症转移并增强了CD8+ T细胞浸润。RNA 测序发现,转移性 CRC 细胞中的 CCL5 转录激活与 T 细胞浸润相关。IFNα而非抗血管内皮生长因子受体2能进一步上调肿瘤中的CCL5。在免疫功能正常的小鼠中,IFNα和抗血管内皮生长因子受体2-IFNα都能通过上调CCL5增加肿瘤浸润CD8+ T细胞亚群。敲除肿瘤细胞中的 CCL5 可减轻 CD8+ T 细胞的浸润,并抑制抗血管内皮生长因子受体 2-IFNα治疗的抗肿瘤效果。因此,我们认为 CCL5 的上调是 IFNα 和基于 IFNα 的免疫细胞因子疗法增强 CD8+ T 细胞浸润转移性 CRC 的关键。这些发现可能有助于开发与 IFNα 相关的免疫细胞因子,用于治疗浸润较少的肿瘤。
Anti-VEGFR2-Interferon α Promotes the Infiltration of CD8+ T Cells in Colorectal Cancer by Upregulating the Expression of CCL5.
SUMMARY
Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.
期刊介绍:
Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.