Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Cell Immunol. 2022 Jan;371:104458. doi: 10.1016/j.cellimm.2021.104458. Epub 2021 Nov 24.
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.
我们之前的工作表明，癌细胞中 SIRT1 的高表达预示着结直肠癌（CRC）预后不良，但它在肿瘤微环境中的作用尚不清楚。在这里，我们检查了表达不同水平 SIRT1 的 CRC 中的肿瘤浸润淋巴细胞（TIL）。我们还建立了一个共培养系统，其中包括单核细胞、CD8 T 细胞和患者来源的肿瘤类器官（PDO），以研究免疫细胞与癌细胞之间的关系。在 SIRT1 高表达（SIRT1-hi）CRC 中，CD8 T 细胞的比例降低，而巨噬细胞的比例增加。共培养结果表明，来自 SIRT1-hi CRC 的肿瘤相关巨噬细胞（TAM）抑制了 CD8 T 细胞的增殖和抗肿瘤活性。重要的是，SIRT1-hi CRC 被证明可以调节 TAM 的迁移和活性。RNA 测序显示，SIRT1-hi 患者中的 CD14 单核细胞表达更高水平的 CXCR4。在机制上，SIRT1 的表达通过抑制 p53 的乙酰化来促进 CXCL12 的表达。我们的研究结果表明，CRC 中的 SIRT1 通过 CXCR4/CXCL12 途径诱导 TAM 迁移，并抑制 CD8 T 细胞的增殖和活性，从而促进 CRC 的进展。
