Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression.
Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression.
复制标题
脉络膜通过分泌CCL5募集和极化肿瘤相关巨噬细胞以促进恶性进展。
DOI：
10.1136/jitc-2023-006808
复制
发表时间：
2023-04
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets. Spectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC). The chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo. Our study implicates that the CCL5–CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5–CCR5 axis is a potential therapeutic target in chordoma.
登录
查看更多内容
影响因子：
29
作者：
Cereijo, Ruben;Gavalda-Navarro, Aleix;Villarroya, Francesc
通讯作者：
Villarroya, Francesc
影响因子：
2.6
作者：
Bongers, Michiel E. R.;Dea, Nicolas;Schwab, Joseph H.
通讯作者：
Schwab, Joseph H.
影响因子：
5.8
作者：
Duan, Wanru;Zhang, Boyan;Chen, Zan
通讯作者：
Chen, Zan
影响因子：
4
作者：
Liu Z;Gao S;Zhu L;Wang J;Zhang P;Li P;Zhang F;Yao W
通讯作者：
Yao W
影响因子：
4.7
作者：
Lopez, Diana C.;Robbins, Yvette L.;Kowalczyk, Joshua T.;Lassoued, Wiem;Gulley, James L.;Miettinen, Markku M.;Gallia, Gary L.;Allen, Clint T.;Hodge, James W.;London Jr, Nyall R.
通讯作者：
London Jr, Nyall R.