PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8+ tumor-infiltrating lymphocytes: highly sensitive detection using phosphor-integrated dot staining

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. For the development of more effective immunotherapies, it is first necessary to elucidate the immunological escape mechanisms. In this study, we applied our recently developed highly sensitive immunostaining method employing fluorescent phosphor-integrated dot (PID) nanoparticles to evaluate the prevalence of programmed death ligand 1 (PD-L1) in patients with PDAC.MethodsThis study included 42 patients with PDAC who underwent pancreatectomy. We evaluated PD-L1 expression in these patients using PID staining and correlated PD-L1 expression level with each patient’s clinico-pathological features.ResultsPD-L1 expression was detected in 61.9% (26/42) of the patients with PDAC by PID staining. There was a significant difference in overall survival between PD-L1-positive and PD-L1-negative patients [hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.00–4.54; P = 0.049]. Among CD8+-tumor-infiltrating lymphocyte-positive cases, the overall survival of PD-L1-positive patients was significantly poorer than that of PD-L1-negative patients (HR 3.84, 95% CI 1.59–10.35; P = 0.003). Univariate and multivariate analyses indicated that PD-L1 expression was an independent predictive poor prognostic factor in patients with PDAC.ConclusionsPD-L1 expression appears to be an important prognostic factor in patients with PDAC who underwent surgical resection.

In-vitro effect of pembrolizumab on different T regulatory cell subsets

“…Yamaki et al . recently reported significantly poorer survival of PD‐L1 + compared to PD‐L1 − in pancreatic ductal adenocarcinoma patients presenting with CD8 + tumour infiltration. Moreover, PD‐1 expression in tumour‐associated macrophages is associated with disease progression in various human malignancies, while PD‐1/PD‐L1 blockade favours macrophage phagocytic activity and suppresses tumour progression .…”

“…The cytotoxic T cell : T reg ratio may be considered as pivotal in immune checkpoint inhibitory therapies, as CD8 1 T cell expansion is associated with better overall survival in various malignancies treated with CTLA-4 and PD-1 blockade [41,42]. Yamaki et al [43] recently reported significantly poorer survival of PD-L1 1 compared to PD-L1 2 in pancreatic ductal adenocarcinoma patients presenting with CD8 1 tumour infiltration. Moreover, PD-1 expression in tumour-associated macrophages is associated with disease progression in various human malignancies, while PD-1/PD-L1 blockade favours macrophage phagocytic activity and suppresses tumour progression [44].…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…The prevalence of therapy resistance to these treatments is a persistent problem. PDAC patients have not benefited from single agent or combination ICI therapy (194)(195)(196) despite increased expression of PD-L1 in tumors (197)(198)(199). Significant efforts are underway to improve immunotherapy efficacy, including studies investigating regulatory B cell inhibition (e.g., Bruton's Tyrosine Kinase (BTK) inhibitors), IDO inhibition, and vaccine therapy (200).…”

Immunotherapy for pancreatic cancer: Barriers and breakthroughs

“…Multiple human studies have indicated that high PD‐L1 expression in pancreatic cancer tumors is associated with worse outcomes suggesting that targeting the PD‐1/PD‐L1 interaction may have therapeutic benefit in these patients . An early preclinical study in a mouse tumor transplant model showed that PD‐1 or PD‐L1 blockade had an anti‐tumor effect which was enhanced when given together with gemcitabine .…”