Department of Gastroenterology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
J Transl Med. 2022 Mar 22;20(1):140. doi: 10.1186/s12967-022-03342-6.
The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients.
We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para-tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured.
Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα or PD1 TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non-HBV-infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis.
Hyperactivated CD47/SIRPα and PD1/PD-L1 signals in CD68 TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.
CD47/SIRPα、PD1/PDL1、CD24/SIGLEC10 和 MHC/LILRB1 的吞噬作用检查点已显示在不同的肿瘤中抑制了巨噬细胞的吞噬作用。然而，在肝内胆管癌（ICC）患者中，吞噬作用检查点及其治疗意义在很大程度上仍不清楚。
我们分析了癌症基因组图谱（TCGA）的测序数据，并鉴定了肿瘤与肿瘤旁组织之间表达不同的基因。然后，我们通过免疫组化（IHC）在 81 名 ICC 患者中检测了 CD68、SIRPα、PD1 和 SIGLEC10 的表达，并测量了这些标志物与不同风险因素的临床意义。
TCGA 数据的肿瘤浸润免疫细胞分析显示巨噬细胞显著增加。进一步分析显示，与癌旁组织相比，ICC 中 M0 巨噬细胞明显升高，M2 巨噬细胞明显降低，而 M1 巨噬细胞没有明显差异。然后，我们检查了一些 M1 和 M2 标志物，发现与癌旁组织相比，ICC 中 M1 标志物（iNOS、TNF、IL12A 和 B）增加，而 M2 标志物（ARG1 和 CD206）减少。此外，CD68、SIRPα、PD1 和 SIGLEC10 的表达显著增加，而 LILRB1 的表达没有增加。我们还通过 IHC 检查了 81 名 ICC 患者中 CD68、SIRPα、PD1 和 SIGLEC10 的表达，结果与 TCGA 数据的结果相似。在分析这些标志物与 ICC 患者进展之间的相关性时，我们发现 CD68、SIRPα 和 PD1 的高表达与 ICC 患者的不良进展相关，而 SIGLEC10 则没有相关性。与非乙型肝炎病毒（HBV）感染患者相比，HBV 感染 ICC 患者的肿瘤组织中观察到更多的 SIRPα 或 PD1 TAMs。多变量分析表明，SIRPα 和 PD1 的表达是 ICC 患者预后的独立指标。
肿瘤组织中 CD68 TAMs 中过度激活的 CD47/SIRPα 和 PD1/PD-L1 信号是 ICC 切除后不良预后的标志物。此外，抗 CD47 联合抗 PD1 或 CD47/PD1 双特异性抗体（BsAb）可能代表 ICC 的有前途的治疗方法。未来还需要进一步研究来证实我们的发现。
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