Martin Wartenberg 1 , Silvia Cibin 1 , Inti Zlobec 1 , Erik Vassella 1 , Serenella Eppenberger-Castori 2 , Luigi Terracciano 2 , Micha David Eichmann 1 , Mathias Worni 3 , Beat Gloor 3 , Aurel Perren 1 , Eva Karamitopoulou 4 Show Affiliations »
Abstract
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. ©2018 American Association for Cancer Research.
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. ©2018 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
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Year: 2018
PMID： 29661773 DOI： 10.1158/1078-0432.CCR-17-3401
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531