PD-L1 expression in liver metastasis: its clinical significance and discordance with primary tumor in colorectal cancer

Abstract

Background: The outcomes of immune checkpoint inhibitors of patients with cancer liver metastases are poor, which may be related to a different tumor microenvironment from primary cancers. This study was aimed to analyze the PD-L1 expression and the immune microenvironment status in liver metastatic diseases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer.Methods: 74 cases of pathologically confirmed colorectal cancer liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. Then, we evaluated the disparity between primary tumor and liver metastasis in PD-L1, CD4 and CD8 density and analyzed the factors associated with obvious disparity.Results: A total of 74 paired colorectal cancer with liver metastases were included in this study. The expression of PD-L1 in liver metastases was positively related to the density of CD4 and CD8. The expression of PD-L1 was higher in liver metastases than in primary tumors in certain subgroups of colorectal cancer, including the patients with concurrent liver metastases (n=63, p=0.05), receiving concurrent resection of primary and metastatic tumors (n=56, p=0.04). The two subgroups generally reflected those without inconsistent external influencing factors, such as treatment and temporal variation, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified, if any. Furthermore, tumor differentiation (moderate vs. poor: OR=0.23, 95% CI: 0.03-0.99, p=0.05)) were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and hepatic metastases.Conclusions: The expression of PD-L1 in the hepatic metastases was higher than in the primary tumors in subgroups reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was closely related to the tumor differentiation.

Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

“…However, this mechanism is utilized by cancers to escape from anti-tumor immunity. Previous study showed that the expression of PD-L1 was increased in liver metastases compared to primary CRC, indicating different intrinsic microenvironment between primary and metastatic CRC [110], which may help CRC liver metastases escape from immune surveillance. In addition, it was reported that chemotherapy can modulate PD-L1 and TIM-3 expression in CRC liver metastases, suggesting the potential strategy of combined chemo-immunotherapies [111].…”

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

“…Wei et al. found that the levels of PD-L1 in liver metastases were higher compared with primary tumors ( 10 ). The immune escape of the tumors was reversed by immune checkpoint inhibitors, novel drugs developed to block these negative feedback pathways by binding to PD-1 (nivolumab, pembrolizumab), PD-L1 (atezolizumab), CTLA-4 (ipilimumab).…”