Stratification of pancreatic ductal adenocarcinoma: Combinatorial genetic, stromal, and immunologic markers

Erik S. Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W. Botros, Vladimir Makarov, Nadeem Riaz, Vinod Balachandran, Steven Leach, Debrah M. Thompson, Timothy A. Chan, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4429-4440
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Genetic Markers
Adenocarcinoma
Biomarkers
Immunosuppressive Agents
Hypoxis
Lymphocytes
Exome
Immune Evasion
Atlases
Immune System Diseases
Immunotherapy
Cluster Analysis
Disease Progression
Neoplasms
Research Design
Therapeutics
Multivariate Analysis
Macrophages
Genome
Staining and Labeling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Stratification of pancreatic ductal adenocarcinoma : Combinatorial genetic, stromal, and immunologic markers. / Knudsen, Erik S.; Vail, Paris; Balaji, Uthra; Ngo, Hoai; Botros, Ihab W.; Makarov, Vladimir; Riaz, Nadeem; Balachandran, Vinod; Leach, Steven; Thompson, Debrah M.; Chan, Timothy A.; Witkiewicz, Agnieszka K.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4429-4440.

Research output: Contribution to journalArticle

Knudsen, ES, Vail, P, Balaji, U, Ngo, H, Botros, IW, Makarov, V, Riaz, N, Balachandran, V, Leach, S, Thompson, DM, Chan, TA & Witkiewicz, AK 2017, 'Stratification of pancreatic ductal adenocarcinoma: Combinatorial genetic, stromal, and immunologic markers', Clinical Cancer Research, vol. 23, no. 15, pp. 4429-4440. https://doi.org/10.1158/1078-0432.CCR-17-0162
Knudsen, Erik S. ; Vail, Paris ; Balaji, Uthra ; Ngo, Hoai ; Botros, Ihab W. ; Makarov, Vladimir ; Riaz, Nadeem ; Balachandran, Vinod ; Leach, Steven ; Thompson, Debrah M. ; Chan, Timothy A. ; Witkiewicz, Agnieszka K. / Stratification of pancreatic ductal adenocarcinoma : Combinatorial genetic, stromal, and immunologic markers. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4429-4440.
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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.

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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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