SIRT1 induces the accumulation of TAMs at colorectal cancer tumor sites via the CXCR4/CXCL12 axis
SIRT1 induces the accumulation of TAMs at colorectal cancer tumor sites via the CXCR4/CXCL12 axis
复制标题
SIRT1 通过 CXCR4/CXCL12 轴诱导 TAM 在结直肠癌肿瘤部位的积累
DOI：
10.1016/j.cellimm.2021.104458
复制
发表时间：
2021-11-27
影响因子：
4.3
通讯作者：
Zhong, Ming
中科院分区：
文献类型：
--
作者：
Fang, Hongsheng;Huang, Yizhou;Zhong, Ming
我们以前的工作表明，癌细胞的SIRT 1高表达预示着不良的结直肠癌（CRC）预后，但其在肿瘤微环境中的作用尚不清楚。在这里，我们检查了CRC中表达不同水平SIRT 1的肿瘤浸润淋巴细胞（TILs）。我们还建立了单核细胞，CD 8（+）T细胞和患者来源的肿瘤类器官（PDO）的共培养系统，以研究免疫细胞和癌细胞之间的关系。SIRT 1高（SIRT 1-hi）CRC中CD 8（+）T细胞百分比降低，巨噬细胞百分比增加。共培养结果显示，来自SIRT 1-hi CRC的肿瘤相关巨噬细胞（TAM）抑制CD 8（+）T细胞的增殖和抗肿瘤活性。重要的是，SIRT 1-hi CRC显示调节TAM的迁移和活性。RNA测序显示SIRT 1-hi患者的CD 14（+）单核细胞表达更高水平的CXCR 4。从机制上讲，SIRT 1表达通过抑制p53的乙酰化来促进CXCL 12的表达。我们的研究结果表明，SIRT 1在CRC中通过CXCR 4/CXCL 12途径诱导TAM迁移，并抑制CD 8（+）T细胞的增殖和活性，从而促进CRC进展。
Our previous work suggested that high SIRT1 expression by cancer cells predicted a poor colorectal cancer (CRC) prognosis, but its role in the tumor microenvironment was unclear.Here, we examined tumor-infiltrating lymphocytes (TILs) in CRC expressing different levels of SIRT1. We also established a co-culture system with monocytes, CD8(+) T cells and patient-derived tumor organoids (PDOs) to study the relationships between immune cells and cancer cells. The percentage of CD8(+) T cells was decreased and the percentage of macrophages was increased in SIRT1-high (SIRT1-hi) CRC. Co-culture results showed that tumor-associated macrophages (TAMs) from SIRT1-hi CRC inhibited the proliferation and anti-tumor activity of CD8(+ )T cells. Importantly, SIRT1-hi CRC were shown to modulate the migration and the activity of TAMs. RNA sequencing revealed that CD14(+ )monocytes in SIRT1-hi patients expressed higher levels of CXCR4. Mechanistically, SIRT1 expression was shown to promote CXCL12 expression by inhibiting the acetylation of p53. Our findings indicate that SIRT1 in CRC induces TAM migration through the CXCR4/CXCL12 pathway, and inhibits the proliferation and activity of CD8(+) T cells, resulting in promotion of CRC progression.