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


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.


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



Alexa Fluor®




Chronic pancreatitis


CXC chemokine ligand 10


CXC chemokine receptor 3




Dulbecco’s modified Eagle’s medium


Ethylenediaminetetraacetic acid


Enzyme-linked immunosorbent assay


Fetal bovine serum


Human leukocyte antigen




Median lethal dose


Natural killer


Overall survival


Pancreatic cancer


Programmed death ligand 1




Primary pancreatic cancer epithelial cells


Positive resection margin


Standard error of the mean


Short tandem repeat


Tumor-associated stroma


University of Florida



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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