Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy

Ruiyu Li; Yangzhige He; Hui Zhang; Jing Wang; Xiaoding Liu; Hangqi Liu; Huanwen Wu; Zhiyong Liang

doi:10.3389/fimmu.2021.690056

Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy

Front Immunol. 2021 Jul 15:12:690056. doi: 10.3389/fimmu.2021.690056. eCollection 2021.

Authors

Ruiyu Li¹, Yangzhige He², Hui Zhang¹, Jing Wang¹, Xiaoding Liu¹, Hangqi Liu¹, Huanwen Wu¹, Zhiyong Liang¹

Affiliations

¹ Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.

Abstract

Background: Pancreatic 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.

Methods: A 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.

Results: Approximately 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.

Conclusions: By 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.

Keywords: immune molecular subtypes; immunogenomics; immunotherapy; non-negative matrix factorization; pancreatic ductal adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't
Validation Study

MeSH terms

Biomarkers, Tumor / genetics*
Carcinoma, Pancreatic Ductal / genetics*
Carcinoma, Pancreatic Ductal / immunology
Carcinoma, Pancreatic Ductal / pathology
Carcinoma, Pancreatic Ductal / therapy
Clinical Decision-Making
Databases, Genetic
Female
Gene Expression Profiling*
Humans
Immunogenetic Phenomena
Immunotherapy
Male
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy
Predictive Value of Tests
Prognosis
Reproducibility of Results
Transcriptome*
Tumor Microenvironment / immunology*

Substances

Biomarkers, Tumor