Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. Immunotherapy has achieved success in the treatment of multiple malignancies. However, the efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. In this research, we aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy.MethodsA training cohort of 149 PDAC samples from The Cancer Genome Atlas (TCGA) with mRNA expression data was analyzed. By means of non-negative matrix factorization (NMF), we virtually dissected the immune-related signals from bulk gene expression data. Detailed immunogenomic and survival analyses of the immune molecular subtypes were conducted to determine their biological and clinical relevance. Validation was performed in five independent datasets on a total of 615 samples.ResultsApproximately 31% of PDAC samples (46/149) had higher immune cell infiltration, more active immune cytolytic activity, higher activation of the interferon pathway, a higher tumor mutational burden (TMB), and fewer copy number alterations (CNAs) than the other samples (all P < 0.001). This new molecular subtype was named Immune Class, which served as an independent favorable prognostic factor for overall survival (hazard ratio, 0.56; 95% confidence interval, 0.33-0.97). Immune Class in cooperation with previously reported tumor and stroma classifications had a cumulative effect on PDAC prognostic stratification. Moreover, programmed cell death-1 (PD-1) inhibitors showed potential efficacy for Immune Class (P = 0.04). The robustness of our immune molecular subtypes was further verified in the validation cohort.ConclusionsBy capturing immune-related signals in the PDAC tumor microenvironment, we reveal a novel molecular subtype, Immune Class. Immune Class serves as an independent favorable prognostic factor for overall survival in PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a 5-year overall survival rate of approximately 9% [1, 2]
Among the different expression patterns determined by non-negative matrix factorization (NMF), one was correlated with a previously reported immune enrichment score reflecting the presence of infiltrating immune cells in tumor tissues (Supplementary Figure 1A) [20]
This expression pattern was regarded as the immune NMF factor, and the top-ranked genes with the highest weight contributing to the immune NMF factor were considered as exemplar genes
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a 5-year overall survival rate of approximately 9% [1, 2]. The emergence of immune checkpoint blockade therapies has shed light on the treatments of PDAC patients. Various predictive biomarkers for immunotherapy have been developed for solid tumors, none have proven their efficacy in PDAC patients [5,6,7]. It is necessary to develop new biomarkers for immunotherapy with particular emphasis on PDAC. Pancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. The efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. We aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy
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