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Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma.

ABSTRACT: 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.

SUBMITTER: Chen X

PROVIDER: S-EPMC8977273 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma.

Chen Xianlong X Mo Shengwei S Zhang Yue Y Ma Heng H Lu Zhaohui Z Yu Shuangni S Chen Jie J

The journal of pathology. Clinical research 20220127 3

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 o ...[more]

PMID: 35083884

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Project description:Immune checkpoint modulation has been a vital therapeutic option in many malignancies, and targeting of novel immune checkpoints, including OX40/OX40L costimulatory signaling, is being assessed in clinical trials. However, little is known about the role of OX40 and OX40L in pancreatic ductal adenocarcinoma (PDAC). Thus, we investigated the clinical significance of OX-40 and OX40L and their associations with alternative immune checkpoints, immune infiltrates, clinicopathological features, and clinical outcomes. We performed multiplexed immunofluorescence staining for OX40, OX40L, CD8, and CD68 using tissue microarrays from 255 patients. Immunohistochemistry data for PD-L1, B7-H3, B7-H4, CD3, and Foxp3 were analyzed. And the RNA sequencing data of OX40/OX40L in The Cancer Genome Atlas and International Cancer Genome Consortium databases were also evaluated. The positive rates for OX40 on tumor cells (TCs) and immune cells (ICs) were 8.6% and 10.2%, respectively, and the positive rates for OX40L on TCs, ICs, and macrophages were 20%, 40.4%, and 12.9%, respectively. OX40 was associated with favorable clinicopathological features. OX40+ on ICs, OX40L+ on TCs, or OX40L+ on macrophages, rather than the total gene and protein levels of OX40/OX40L, were associated with improved survival. OX40+ on ICs and OX40L+ on macrophages were independent factors of clinical outcomes. Moreover, we could more accurately stratify patients through the combination of OX40 on ICs and OX40L on TCs, and patients with OX40+ ICs and OX40L+CK+ showed the best outcome. And we demonstrated that patients with OX40-ICs and low CD8+ T cells infiltration had unfavorable survival. Intriguingly, OX40+ ICs or OX40L+ macrophages demonstrated superior survival in patients with PD-L1 negativity than in those with PD-L1 positivity. Furthermore, OX40+ ICs were correlated with negative B7-H4 on TCs, high densities of CD3 T cells, and high densities of Foxp3 T cells; OX40+ TCs and OX40L+ TCs were associated with low densities of Foxp3 T cells. We identified OX40 and OX40L as promising predictors for prognosis in PDAC.

Project description:BackgroundMost patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial.Materials and methodsThe study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included.ResultsHigh levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy.ConclusionsCirculating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

Dataset Information

Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma.

Publications

Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma.

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