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

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.

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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

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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.

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Correspondence to Shannon M. Wallet or Steven J. Hughes.

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Delitto, D., Perez, C., Han, S. et al. Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer. Cancer Immunol Immunother 64, 1553–1563 (2015). https://doi.org/10.1007/s00262-015-1760-y

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Keywords

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