title: Immunologic and Metabolic Features of Pancreatic Ductal Adenocarcinoma Define Prognostic Subtypes of Disease.
abstract: Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive microenvironment that supports the growth of the malignancy as well as immune system evasion. Here we examine markers of immunosuppression in PDA within the context of the glycolytic tumor microenvironment, their interrelationship with tumor biology and association with overall survival.
  
  
  
  We utilized tissue microarrays consisting of 223 PDA patients annotated for clinical stage, tumor size, lymph node involvement, and survival. Expression of CD163, FoxP3, PD-L1, and MCT4 was assessed by IHC and statistical associations were evaluated by univariate and multivariate analysis. Multimarker subtypes were defined by random forest analysis. Mechanistic interactions were evaluated using PDA cell lines and models for myeloid differentiation.
  
  
  
  PDA exhibits discrete expression of CD163, FoxP3, and PD-L1 with modest individual significance. However, combined low expression of these markers was associated with improved prognosis (P = 0.02). PDA tumor cells altered macrophage phenotype and function, which supported enhanced invasiveness in cell-based models. Lactate efflux mediated by MCT4 was associated with, and required for, the selective conversion of myeloid cells. Correspondingly, MCT4 expression correlated with immune markers in PDA cases, and increased the significance of prognostic subtypes (P = 0.002).
  
  
  
  There exists a complex interplay between PDA tumor cells and the host immune system wherein immunosuppression is associated with negative outcome. MCT4 expression, representative of the glycolytic state of PDA, contributes to the phenotypic conversion of myeloid cells. Thus, metabolic status of PDA tumors is an important determinant of the immunosuppressive environment. Clin Cancer Res; 22(14); 3606-17. ©2016 AACR.
authors: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas.
authors: Jack
authors: J
authors: Hutcheson
authors: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas.
authors: Uthra
authors: U
authors: Balaji
authors: Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas. Department of Surgery, UT Southwestern Medical Center, Dallas, Texas.
authors: Matthew R
authors: MR
authors: Porembka
authors: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
authors: Megan B
authors: MB
authors: Wachsmann
authors: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Peter A
authors: PA
authors: McCue
authors: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
authors: Erik S
authors: ES
authors: Knudsen
authors: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas. Department of Pathology, UT Southwestern Medical Center, Dallas, Texas. agnes.witkiewicz@utsouthwestern.edu.
authors: Agnieszka K
authors: AK
authors: Witkiewicz
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism*; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D060890:B7-H1 Antigen; D015415:Biomarkers; D000098902:CD163 Antigen; D051858:Forkhead Transcription Factors; D011956:Receptors, Cell Surface