Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Clin Cancer Res. 2018 Sep 15;24(18):4444-4454. doi: 10.1158/1078-0432.CCR-17-3401. Epub 2018 Apr 16.


Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings.Experimental Design: A well-characterized PDAC cohort (n = 110) underwent next-generation sequencing with a hot spot cancer panel while next-generation tissue microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM), and DNA mismatch repair proteins. Previous data on FOXP3 were integrated. Immune cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8th edition, 2017), survival, and epithelial-mesenchymal transition (EMT)-like tumor budding.Results: Three PDAC subtypes were identified: the "immune escape" (54%), poor in T and B cells and enriched in FOXP3+ regulatory T cells (Treg), with high-grade budding, frequent CDKN2A, SMAD4, and PIK3CA mutations, and poor outcome; the "immune rich" (35%), rich in T and B cells and poorer in FOXP3+ Tregs, with infrequent budding, lower CDKN2A and PIK3CA mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11 and ATM), and the best outcome; and the "immune exhausted" (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high PIK3CA mutation rate and a microsatellite-unstable subpopulation with a high prevalence of JAK3 mutations. The combination of low budding, low stromal FOXP3 counts, presence of TLTs, and absence of CDKN2A mutations confers significant survival advantage in patients with PDAC.Conclusions: Immune host responses correlate with tumor characteristics, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance. Clin Cancer Res; 24(18); 4444-54. ©2018 AACRSee related commentary by Khalil and O'Reilly, p. 4355.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Forkhead Transcription Factors / genetics*
  • Genomics*
  • Humans
  • Immunophenotyping
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / genetics
  • Pancreatic Neoplasms / classification
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • T-Lymphocytes, Regulatory / immunology


  • Biomarkers, Tumor
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Neoplasm Proteins