title: Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment.
abstract: OBJECTIVE
  The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA.
  
  
  METHODS
  We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood.
  
  
  RESULTS
  In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg.
  
  
  CONCLUSIONS
  Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Kendall C
authors.initials: KC
authors.lastname: Shibuya
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Goel
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Sham
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Pollack
authors.affiliation: Surgical Oncology, Seattle Cancer Care Alliance, Seattle, Washington, United States of America.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Leahy
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Whiting
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Cassian
authors.initials: C
authors.lastname: Yee
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Venu G
authors.initials: VG
authors.lastname: Pillarisetty
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D020381:Interleukin-17; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor