Siglec‐15, a novel immune checkpoint, is an emerging target for next‐generation cancer immunotherapy. However, the role of Siglec‐15 in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. We investigated the expression of Siglec‐15 and its association with clinicopathological characteristics, programmed cell death‐ligand 1 (PD‐L1), immune cells, and DNA damage repair (DDR) molecules in a cohort of 291 patients with PDAC. Positive tumour cell expression of Siglec‐15 and PD‐L1 was observed in 18.6 and 30.3% of the samples, respectively. We also detected Siglec‐15 positivity in macrophages in 3.4% of patients. Co‐expression of Siglec‐15 with PD‐L1 was observed in 6.1% of the patients. A total of 33 PD‐L1‐negative samples (18.0%) were Siglec‐15‐positive. Siglec‐15 was observed more frequently in moderate‐to‐well‐differentiated tumours. Siglec‐15 was associated with a low density of Tregs and CD45RO T cells, high BRCA1 expression, and improved survival. Both Siglec‐15 and PD‐L1 are independent factors of patient outcomes. The prognostic significance of Siglec‐15 for survival was more discriminative in lymph node‐negative, high BRCA1 expression, or low BRCA2 expression tumours than in lymph node‐positive, low BRCA1 expression, or high BRCA2 expression tumours. In conclusion, we identified Siglec‐15 as a promising predictor for prognosis combined with different DDR molecular statuses and complex tumour‐infiltrating cells in PDAC. Targeting Siglec‐15 may be a novel therapeutic option for patients who are unresponsive to anti‐PD‐1 therapy. Future studies are needed to validate the prognostic significance of Siglec‐15 and to investigate its regulatory mechanisms in this disease.
Immunotherapy targeting programmed cell death-1 (PD-1) has considerably improved the prognosis of patients with advanced cancers; however, its efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC) is unfavourable. To address the issue of PDAC immunotherapy, we investigated the expression of two PD-1 ligands, PD-L1 and PD-L2, in PDAC, analysed their role in survival, and explored their correlation with clinicopathological features, immune infiltration, and DNA damage response molecules. Immunohistochemistry was performed on 291 surgically resected PDAC samples. In tumour cells (TCs) and immune cells (ICs), the positivity of PD-L1 expression was 30 and 20% and that of PD-L2 expression was 40 and 20%, respectively. Moreover, PD-L1 expression on TCs correlated with its expression on ICs (p < 0.0001); a similar result was observed for PD-L2 (p < 0.0001). Nonetheless, no correlation was observed between PD-L1 and PD-L2 expression. Positive PD-L1 expression on TCs was related to N1 stage (p = 0.011) and AJCC II stage (p = 0.002), whereas positive PD-L2 expression on TCs was associated with high FOXP3 + cell infiltration (p = 0.001) and high BRCA2 expression (p < 0.0001). Survival analysis revealed that positive PD-L1 (p = 0.046) and PD-L2 (p = 0.028) expression on TCs was an independent risk factor for unfavourable disease-specific survival (DSS). Furthermore, positive PD-L2 expression on TCs was an independent risk factor for lower DSS in the pN0 (p = 0.023), moderate and well tumour differentiation (p = 0.004), low BRCA1 (p = 0.017), wild-type p53 (p = 0.034), and proficient mismatch repair (p = 0.004) subgroups. Moreover, post-operative adjuvant chemotherapy could significantly affect DSS, regardless of PD-L1/PD-L2 expression status (positive or negative) on TCs, while it only prolonged DSS in PDL1-ICs (À) (p < 0.0001) and PDL2-ICs (À) (p < 0.0001) subgroups. This study provides a comprehensive understanding of the roles of PD-L1 and PD-L2 in PDAC, supporting anti-PD-1 axis immunotherapy for PDAC.
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