Department of Gastrointestinal Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Central Laboratory, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
J Immunother Cancer. 2022 Sep;10(9). doi: 10.1136/jitc-2021-004219.
Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression.
CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages.
CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155 TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155 macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155 bone marrow transplantation in wild-type mice, as well as CD155- macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155 TAMs.
These findings indicated that CD155 TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155 TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.
免疫原性分子 CD155 在包括结直肠癌（CRC）在内的各种肿瘤微环境（TME）中过度表达。肿瘤相关巨噬细胞（TAMs）是 CRC TME 中最丰富的免疫细胞，在 CRC 进展和转移中发挥着至关重要的作用。大多数研究都集中在研究 CRC 细胞特异性 CD155 在 CRC 进展中的作用，而 TAMs 特异性 CD155 的贡献仍不清楚。在这里，我们试图研究 CD155 在 CRC TAMs 中的表达模式及其在肿瘤免疫和进展中的作用。
使用流式细胞术分析 50 例 CRC 患者肿瘤组织和癌旁组织中 CD155 在 CRC TAMs 中的表达模式，并使用免疫组织化学法分析 141 例 CRC 患者肿瘤组织中 CD155 的表达。分析 TAMs 中 CD155 表达水平与 M1 和 M2 表型转化的相关性。在体外和体内研究巨噬细胞特异性 CD155 在 CRC 进展和肿瘤免疫反应中的作用。我们进一步分析了 CRC 细胞对巨噬细胞中 CD155 表达调节的影响。
临床样本中的 CRC TAMs 表现出比癌旁组织和相邻正常组织中的巨噬细胞更强的 CD155 表达。III/IV 期 CRC 的 CD155 表达水平高于 I/II 期，且与 CRC 患者的生存呈负相关。CD155 TAMs 表现出 M2 表型，并且白细胞介素（IL）-10 和转化生长因子（TGF）-β表达水平更高。CD155 巨噬细胞促进 CRC 细胞迁移、侵袭和肿瘤生长，支持临床组织分析的结果。这种作用主要通过 TGF-β 诱导的 STAT3 激活介导的 CRC 细胞中基质金属蛋白酶（MMP）2 和 MMP9 的释放来调节。野生型小鼠的 CD155 骨髓移植以及 CD155-巨噬细胞治疗促进了异位 CRC 模型中小鼠的抗肿瘤免疫反应。此外，CRC 细胞释放 IL-4 以触发巨噬细胞中 CD155 的表达，表明 CRC 细胞在 CD155 TAMs 发育中的调节作用。
这些发现表明，CD155 TAMs 是 CRC 中 M2 表型转化、免疫抑制和肿瘤进展的罪魁祸首。CRC 组织中 CD155 TAMs 的特定定位可能成为 CRC 治疗的潜在治疗靶点。
