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Cancer Immunology, Immunotherapy

, Volume 64, Issue 12, pp 1553–1563 | Cite as

Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer

  • Daniel Delitto
  • Chelsey Perez
  • Song Han
  • David H. Gonzalo
  • Kien Pham
  • Andrea E. Knowlton
  • Christina L. Graves
  • Kevin E. Behrns
  • Lyle L. Moldawer
  • Ryan M. Thomas
  • Chen Liu
  • Thomas J. GeorgeJr.
  • Jose G. Trevino
  • Shannon M. WalletEmail author
  • Steven J. HughesEmail author
Original Article

Abstract

The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival.

Keywords

Interferon-γ CXCL10 Pancreatic cancer Epithelial cell Tumor-associated stroma Immuno-oncology 

Abbreviations

AF

Alexa Fluor®

APC

Allophycocyanin

CP

Chronic pancreatitis

CXCL10

CXC chemokine ligand 10

CXCR3

CXC chemokine receptor 3

DAPI

4′,6-diamidino-2-phenylindole

DMEM

Dulbecco’s modified Eagle’s medium

EDTA

Ethylenediaminetetraacetic acid

ELISA

Enzyme-linked immunosorbent assay

FBS

Fetal bovine serum

HLA

Human leukocyte antigen

IFNγ

Interferon-γ

LD50

Median lethal dose

NK

Natural killer

OS

Overall survival

PC

Pancreatic cancer

PDL1

Programmed death ligand 1

PE

Phycoerythrin

PPCE

Primary pancreatic cancer epithelial cells

R1

Positive resection margin

SEM

Standard error of the mean

STR

Short tandem repeat

TAS

Tumor-associated stroma

UF

University of Florida

Notes

Acknowledgments

We would like to thank the National Cancer Institute (NCI 5T32 CA106493-09), the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK F31 DK104492-01A), the National Institute of Dental and Craniofacial Research (NIDCR T90 DE021990-02), the Cracchiolo Foundation and the Frederick A. Coller Surgical Society for their support in these investigations.

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.

Supplementary material

262_2015_1760_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1810 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Daniel Delitto
    • 1
  • Chelsey Perez
    • 1
  • Song Han
    • 1
  • David H. Gonzalo
    • 2
  • Kien Pham
    • 2
  • Andrea E. Knowlton
    • 3
  • Christina L. Graves
    • 3
  • Kevin E. Behrns
    • 1
  • Lyle L. Moldawer
    • 1
  • Ryan M. Thomas
    • 1
  • Chen Liu
    • 2
  • Thomas J. GeorgeJr.
    • 4
  • Jose G. Trevino
    • 1
  • Shannon M. Wallet
    • 3
    Email author
  • Steven J. Hughes
    • 1
    Email author
  1. 1.Department of Surgery, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Department of Pathology, Immunology, Laboratory MedicineUniversity of FloridaGainesvilleUSA
  3. 3.Department of Oral Biology, College of DentistryUniversity of FloridaGainesvilleUSA
  4. 4.Department of MedicineUniversity of FloridaGainesvilleUSA

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