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Hepato-pancreato-biliary

P30: Aryl Hydrocarbon Receptor Ligands Found in Cigarette Smoke Drive Pancreatic Cancer Via Pro-Tumorigenic T Cell Polarization

    ePoster Presenter(s)

  • Brian D. Griffith, MD (he/him/his)

    General Surgery Resident
    Department of Surgery, University of Michigan
    Ann Arbor, Michigan, United States

    • Submitter(s)

  • Brian D. Griffith, MD (he/him/his)

    General Surgery Resident
    Department of Surgery, University of Michigan
    Ann Arbor, Michigan, United States

    • Author(s)

  • Brian D. Griffith, MD (he/him/his)

    General Surgery Resident
    Department of Surgery, University of Michigan
    Ann Arbor, Michigan, United States

  • PK

    Padma Kadiyala, BS

    PhD Candidate
    Department of Immunology, University of Michigan, United States

  • JM

    Jake McGue, BS

    Laboratory Technician
    Department of Surgery, University of Michigan, United States

  • LS

    Lei Sun, PhD

    Senior Scientist
    Department of Surgery, University of Michigan, United States

  • AK

    Aadith Kumar, n/a

    Laboratory Technician
    Department of Surgery, University of Michigan, United States

  • CE

    Carlos Espinoza, MS

    Research Lab Specialist
    Department of Surgery, University of Michigan, United States

  • JE

    Jacob Edwards, BS

    Laboratory Technician
    Department of Surgery, University of Michigan, United States

  • KD

    Katelyn Donahue, BS

    PhD Candidate
    Cancer Biology Program, University of Michigan, United States

  • YZ

    Yaqing Zhang, PhD

    Research Assistant Professor
    Department of Surgery, University of Michigan, United States

  • CC

    Clifford S. Cho, MD

    C. Gardner Child Professor of Surgery
    Department of Surgery, University of Michigan
    Ann Arbor, Michigan, United States

  • MP

    Marina Pasca di Magliano, PhD

    Maud T. Lane Professor of Surgical Immunology
    Departments of Surgery and Cell Biology, University of Michigan, United States

  • Timothy L. Frankel, MD, FACS

    Maud T Lane Professor of Surgical Oncology
    Department of Surgery, University of Michigan; Department of Surgery, Ann Arbor Veterans Affairs Healthcare System, United States

Introduction: Interleukin-22 (IL22) promotes pancreatic ductal adenocarcinoma (PDAC). IL22 producing cells rely upon the aryl hydrocarbon receptor (AhR) for activation and differentiation. Prototypical AhR ligands (AhRLs) like 2,3,7,8-tetrachlorodibenzo-p-dixoin (TCDD) are commonly found in cigarette smoke. As smoking doubles the risk of PDAC, we aimed to investigate the role of TCDD and AhR activation on IL22 signaling in PDAC.

Methods: Naïve CD4 T cells were treated with TCDD and an AhR inhibitor in vitro, and RNA expression and protein concentration quantified. PDAC tumor cells were implanted into pancreata of mice and treated with TCDD or vehicle for 19 days. Transgenic mouse models were used to assess AhR and IL22 dependence. Tumor volume and RNA expression were measured. Immune infiltration was quantified with multiplex fluorescent immunohistochemistry (mfIHC). Transcriptomic profiles were analyzed with single cell RNA sequencing (scRNA-seq).

Results: TCDD polarized naïve CD4 cells towards a T helper (Th)22 phenotype as seen by increased IL22 RNA and protein expression in vitro, which was AhR-dependent. In an orthotopic model, TCDD increased tumor volume, IL22 expression, and Cyp1a1 expression, a marker of AhR activation, over vehicle in wild-type (WT) mice. Systemic knockout of IL22 (IL22-/-) partially abrogated the TCDD-mediated increase in PDAC size. Analysis of immune infiltration in WT mice showed increased CD4+ regulatory T cells (Tregs) with TCDD. Inducible depletion of FoxP3+ Tregs (Foxp3tm3(DTR/GFP)Ayr) partially abrogated the TCDD-mediated increase in tumor size. CD4-specific AhR knockout (AhRf/f;CD4-Cre) confirmed a decrease in tumor size, IL22 expression, and Treg infiltration with TCDD relative to WT. scRNA-seq showed a higher proportion of Th17/Th22 cells and Tregs and a lower proportion of effector CD8 T cells (CTLs) with TCDD in WT mice. In a spontaneous model, 3 weeks of TCDD in mice with an oncogenic Kras mutation (KrasLSL.G12D/+;Pdx1-Cre) increased the frequency and grade of pre-neoplastic PanIN lesions. mfIHC analysis showed a higher proportion of Tregs and decreased distance between Tregs and CTLs.

Conclusions: The AhRL TCDD found in cigarette smoke promotes pancreatic dysplasia and PDAC progression through increased IL22 signaling, increased Treg infiltration, and decreased CTL function, suggesting polarization of CD4 T cells to pro-tumorigenic Th22s and Tregs. Inhibition of AhR may serve as a therapeutic modality to repolarizing T cells to a more pro-inflammatory phenotype.

Learning Objectives:

  • Upon completion, participants will be able to describe the role of interleukin-22 in pancreatic cancer progression.
  • Upon completion, participants will be able to describe a role of regulatory T cells in pancreatic cancer progression.
  • Upon completion, participants will be able to define the influence of aryl hydrocarbon receptor activation on T cell function in pancreatic cancer.