PMID- 26423423 OWN - NLM STAT- MEDLINE DCOM- 20160229 LR - 20221207 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 64 IP - 12 DP - 2015 Dec TI - Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer. PG - 1553-63 LID - 10.1007/s00262-015-1760-y [doi] AB - The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-gamma (IFNgamma) 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 IFNgamma remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNgamma response within and on key cells of the PC microenvironment was evaluated. IFNgamma 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, IFNgamma 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 IFNgamma has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival. FAU - Delitto, Daniel AU - Delitto D AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Perez, Chelsey AU - Perez C AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Han, Song AU - Han S AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Gonzalo, David H AU - Gonzalo DH AD - Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. FAU - Pham, Kien AU - Pham K AD - Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. FAU - Knowlton, Andrea E AU - Knowlton AE AD - Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. FAU - Graves, Christina L AU - Graves CL AD - Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. FAU - Behrns, Kevin E AU - Behrns KE AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Moldawer, Lyle L AU - Moldawer LL AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Thomas, Ryan M AU - Thomas RM AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Liu, Chen AU - Liu C AD - Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. FAU - George, Thomas J Jr AU - George TJ Jr AD - Department of Medicine, University of Florida, Gainesville, FL, USA. FAU - Trevino, Jose G AU - Trevino JG AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. FAU - Wallet, Shannon M AU - Wallet SM AD - Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. swallet@dental.ufl.edu. FAU - Hughes, Steven J AU - Hughes SJ AD - Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. steven.hughes@surgery.ufl.edu. LA - eng GR - T90 DE021990/DE/NIDCR NIH HHS/United States GR - 5T32 CA106493-09/CA/NCI NIH HHS/United States GR - F31 DK104492-01A/DK/NIDDK NIH HHS/United States GR - T32 CA106493/CA/NCI NIH HHS/United States GR - R01 DE019783/DE/NIDCR NIH HHS/United States GR - T90 DE021990-02/DE/NIDCR NIH HHS/United States GR - F31 DK104492/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150930 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Chemokine CXCL10) RN - 0 (HLA Antigens) RN - 0 (Receptors, CXCR3) RN - 0W860991D6 (Deoxycytidine) RN - 82115-62-6 (Interferon-gamma) RN - 9008-11-1 (Interferons) RN - 0 (Gemcitabine) SB - IM MH - Adaptive Immunity/genetics/immunology MH - Cell Line, Tumor MH - Chemokine CXCL10/genetics/metabolism MH - Deoxycytidine/*analogs & derivatives/pharmacology MH - Drug Resistance, Neoplasm/genetics MH - Enzyme-Linked Immunosorbent Assay MH - Flow Cytometry MH - Gene Expression Regulation, Neoplastic/drug effects MH - HLA Antigens/genetics MH - Humans MH - Interferon-gamma/pharmacology MH - Interferons/*immunology MH - Pancreatic Neoplasms/diagnosis/*physiopathology MH - Receptors, CXCR3/genetics MH - Tumor Cells, Cultured MH - Tumor Microenvironment/*physiology MH - Gemcitabine PMC - PMC5129167 MID - NIHMS830192 OTO - NOTNLM OT - CXCL10 OT - Epithelial cell OT - Immuno-oncology OT - Interferon-gamma OT - Pancreatic cancer OT - Tumor-associated stroma COIS- All authors declare no conflicts of interest. EDAT- 2015/10/02 06:00 MHDA- 2016/03/02 06:00 PMCR- 2015/09/30 CRDT- 2015/10/02 06:00 PHST- 2015/06/26 00:00 [received] PHST- 2015/09/17 00:00 [accepted] PHST- 2015/10/02 06:00 [entrez] PHST- 2015/10/02 06:00 [pubmed] PHST- 2016/03/02 06:00 [medline] PHST- 2015/09/30 00:00 [pmc-release] AID - 10.1007/s00262-015-1760-y [pii] AID - 1760 [pii] AID - 10.1007/s00262-015-1760-y [doi] PST - ppublish SO - Cancer Immunol Immunother. 2015 Dec;64(12):1553-63. doi: 10.1007/s00262-015-1760-y. Epub 2015 Sep 30.