TY - JOUR
T1 - Stratification of pancreatic ductal adenocarcinoma
T2 - Combinatorial genetic, stromal, and immunologic markers
AU - Knudsen, Erik S.
AU - Vail, Paris
AU - Balaji, Uthra
AU - Ngo, Hoai
AU - Botros, Ihab W.
AU - Makarov, Vladimir
AU - Riaz, Nadeem
AU - Balachandran, Vinod
AU - Leach, Steven
AU - Thompson, Debrah M.
AU - Chan, Timothy A.
AU - Witkiewicz, Agnieszka K.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy. Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance. Results: PDAC cases exhibited distinct stromal phenotype that were associated with prognosis, glycolytic and hypoxi biomarkers, and immune infiltrate composition. Immun infiltrate was diverse among PDAC cases and enrichment fo M2 macrophages and select immune checkpoints regulator were specifically associated with survival. Composite analysi with neoantigen burden, immunologic, and stromal feature defined novel subtypes of PDAC that could have bearin on sensitivity to immunologic therapy approaches. In addi tion, a subtype with low levels of neoantigens and minima lymphocyte infiltrate was associated with improved overal survival. Conclusions: The mutational burden of PDAC is asso ciated with distinct immunosuppressive mechanisms tha are conditioned by the tumor stromal environment. Th defined subtypes have significance for utilizing immuno therapy in the treatment of PDAC.
AB - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy. Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance. Results: PDAC cases exhibited distinct stromal phenotype that were associated with prognosis, glycolytic and hypoxi biomarkers, and immune infiltrate composition. Immun infiltrate was diverse among PDAC cases and enrichment fo M2 macrophages and select immune checkpoints regulator were specifically associated with survival. Composite analysi with neoantigen burden, immunologic, and stromal feature defined novel subtypes of PDAC that could have bearin on sensitivity to immunologic therapy approaches. In addi tion, a subtype with low levels of neoantigens and minima lymphocyte infiltrate was associated with improved overal survival. Conclusions: The mutational burden of PDAC is asso ciated with distinct immunosuppressive mechanisms tha are conditioned by the tumor stromal environment. Th defined subtypes have significance for utilizing immuno therapy in the treatment of PDAC.
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U2 - 10.1158/1078-0432.CCR-17-0162
DO - 10.1158/1078-0432.CCR-17-0162
M3 - Article
C2 - 28348045
AN - SCOPUS:85024491228
SN - 1078-0432
VL - 23
SP - 4429
EP - 4440
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -