The Significance and Relationship Between Siglec15 and PD-L1 in Colon Adenocarcinoma

Abstract

Background: Siglec15 is considered as a novel immune checkpoint and an emerging target for next-generation cancer immunotherapy. However, the role of Siglec15 and its relationship with PD-L1 in colon adenocarcinoma (COAD) is still elusive. This study aimed to investigate the prognostic impact of Siglec15 expression and its relationship with PD-L1 and tumor-infiltrating lymphocytes (TILs) in COAD, and in microsatellite stable (MSS) COAD.

Methods: We evaluated the expression levels of Siglec15 and PD-L1, in tumor stroma cells, cancer cells or the whole cells, in cancer tissues from cases with surgically resectable primary COAD by immunohistochemistry. We analyzed the association of Siglec15 with PD-L1 expression, and the association of them with CD8⁺ or CD4⁺ T cell density in tumor tissue, respectively.

Findings: The positive rates of Siglec15 expression were 55.9% (tumor stroma, TS), 64.7% (cancer cells, CC) and 58.8% (whole), respectively. Siglec15 was significantly higher expression in COAD than normal tissue, and elevated Siglec15(TS), rather than Siglec15(CC) and Siglec15(whole), correlated with poor prognosis. Siglec15(TS) expression was inversely with the density of CD8⁺ T cell, but not CD4⁺ T cell in COAD and MSS COAD. Moreover, Siglec15(TS) protein expression was exclusive to PD-L1(TS), while there were positive correlations between Siglec15(CC) and PD-L1(CC), and Siglec15(whole) and PD-L1(whole). A new immune classification, based on Siglec15(TS)/PD-L1(TS) expression, indicating that patients with Siglec15(TS)^-/PD-L1(TS)⁺ status had the longest survival.

Interpretation: Siglec15(TS) is an independent predictor for prognosis and inversely associated with CD8⁺ T cell density in COAD and MSS COAD tissue. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for COAD in the future.

Funding: This work was supported by the National Key R&D Program of China (2019YFC1316003), the National Nature Science Foundation in China (NSFC) (81974369 and 82103080), the National Postdoctoral Program for Innovative Talents (BX2021392), and the China Postdoctoral Science Foundation (2021M693652).

Declaration of Interest: The authors declare no competing interests.

Ethical Approval: All patients signed an informed consent before surgery that permitted the usage of resected tumors and clinical profiles in research, under the condition of anonymity. The human tissue specimen research was approved by the institutional ethics committee of Shanghai Outdo Biotech Co, Shanghai, China (Exp. number: YB M-05-02).

Keywords: Siglec15, PD-L1, immunotherapy, colon adenocarcinoma