title: Synergistic COX2 Induction by IFNγ and TNFα Self-Limits Type-1 Immunity in the Human Tumor Microenvironment.
abstract: Maintenance of CTL-, Th1-, and NK cell-mediated type-1 immunity is essential for effective antitumor responses. Unexpectedly, we observed that the critical soluble mediators of type-1 immune effector cells, IFNγ and TNFα, synergize in the induction of cyclooxygenase 2 (COX2), the key enzyme in prostaglandin (PG)E2 synthesis, and the subsequent hyperactivation of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (TME) of ovarian cancer patients. MDSC hyperactivation by type-1 immunity and the resultant overexpression of indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS/NOS2), IL10, and additional COX2 result in strong feedback suppression of type-1 immune responses. This paradoxical immune suppression driven by type-1 immune cell activation was found to depend on the synergistic action of IFNγ and TNFα, and could not be reproduced by either of these factors alone. Importantly, from a therapeutic standpoint, these negative feedback limiting type-1 responses could be eliminated by COX2 blockade, allowing amplification of type-1 immunity in the ovarian cancer TME. Our data demonstrate a new mechanism underlying the self-limiting nature of type-1 immunity in the human TME, driven by the synergistic induction of COX2 by IFNγ and TNFα, and provide a rationale for targeting the COX2-PGE2 axis to enhance the effectiveness of cancer immunotherapies.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wong
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.affiliation: Departments of Gynecological Oncology and Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Magee-Womens Research Institute, Ovarian Cancer Center of Excellence, Pittsburgh, Pennsylvania. Peritoneal/Ovarian Cancer Specialty Care Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania. kalinskip@upmc.edu.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D015415:Biomarkers; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007109:Immunity; D056747:Immunomodulation; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D015232:Dinoprostone
references.citation: Cancer J. 2010 Jul-Aug;16(4):348-53
references.pmid: 20693846
references.citation: N Engl J Med. 2003 Jan 16;348(3):203-13
references.pmid: 12529460
references.citation: Clin Cancer Res. 2011 Oct 1;17(19):6118-24
references.pmid: 21705455
references.citation: Clin Cancer Res. 2003 Oct 1;9(12):4347-55
references.pmid: 14555505
references.citation: Cancer Res. 2011 Dec 15;71(24):7463-70
references.pmid: 22025564
references.citation: J Exp Med. 2007 Jun 11;204(6):1463-74
references.pmid: 17548519
references.citation: Am J Transl Res. 2014 Jan 15;6(2):114-8
references.pmid: 24489990
references.citation: J Immunother. 2011 Apr;34(3):270-8
references.pmid: 21389871
references.citation: Cell. 2015 Sep 10;162(6):1257-70
references.pmid: 26343581
references.citation: J Immunol. 2007 Jul 15;179(2):977-83
references.pmid: 17617589
references.citation: J Immunol. 2013 Apr 1;190(7):3783-97
references.pmid: 23440412
references.citation: J Exp Med. 1999 Jan 18;189(2):219-30
references.pmid: 9892605
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):214-22
references.pmid: 16397045
references.citation: Trends Immunol. 2003 Jun;24(6):302-6
references.pmid: 12810105
references.citation: J Immunol. 2005 Nov 1;175(9):6169-76
references.pmid: 16237114
references.citation: Nat Rev Immunol. 2012 Apr;12(4):253-68
references.pmid: 22437938
references.citation: J Exp Med. 2001 Jun 4;193(11):1261-8
references.pmid: 11390433
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: J Exp Med. 2005 Oct 3;202(7):941-53
references.pmid: 16203865
references.citation: Nat Rev Cancer. 2009 May;9(5):361-71
references.pmid: 19343034
references.citation: Blood. 2008 Apr 15;111(8):4233-44
references.pmid: 18272812
references.citation: Semin Immunopathol. 2013 Mar;35(2):123-37
references.pmid: 22996682
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Oncoimmunology. 2015 Aug 12;5(2):e1074374
references.pmid: 27057439
references.citation: J Clin Oncol. 2010 May 10;28(14):2460-6
references.pmid: 20385998
references.citation: Cancer Immunol Immunother. 2012 Jul;61(7):1019-31
references.pmid: 22146893
references.citation: J Immunol. 2005 Jul 15;175(2):813-9
references.pmid: 16002678
references.citation: Nat Med. 2004 Oct;10(10):1088-94
references.pmid: 15448685
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: N Engl J Med. 2011 Jun 30;364(26):2517-26
references.pmid: 21639810
references.citation: Nat Rev Cancer. 2012 Apr;12(4):252-64
references.pmid: 22437870
references.citation: Lancet Oncol. 2013 May;14(6):e218-28
references.pmid: 23639322
references.citation: J Exp Med. 2012 Feb 13;209(2):201-9
references.pmid: 22330682
references.citation: J Clin Invest. 2006 Oct;116(10):2777-90
references.pmid: 17016559
references.citation: J Immunol. 2012 Jan 1;188(1):21-8
references.pmid: 22187483
references.citation: Blood. 2011 Nov 17;118(20):5498-505
references.pmid: 21972293
references.citation: J Exp Med. 2002 Feb 18;195(4):473-83
references.pmid: 11854360
references.citation: J Immunol. 2002 Jan 15;168(2):689-95
references.pmid: 11777962
references.citation: Sci Transl Med. 2012 Mar 28;4(127):127ps8
references.pmid: 22461638
references.citation: Int J Cancer. 2006 May 1;118(9):2220-31
references.pmid: 16331615
references.citation: Mol Hum Reprod. 2000 Apr;6(4):369-74
references.pmid: 10729320
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
references.pmid: 16344461
references.citation: Nat Rev Cancer. 2012 Apr;12(4):298-306
references.pmid: 22419253
references.citation: Cancer Res. 2007 May 1;67(9):4507-13
references.pmid: 17483367
references.citation: Sci Transl Med. 2012 Mar 28;4(127):127ra37
references.pmid: 22461641
references.citation: Cancer Res. 2013 Jul 1;73(13):3877-87
references.pmid: 23633486
references.citation: N Engl J Med. 2010 Jul 29;363(5):411-22
references.pmid: 20818862
references.citation: Nat Rev Immunol. 2003 Dec;3(12):984-93
references.pmid: 14647480
references.citation: Nat Rev Drug Discov. 2011 Aug;10(8):591-600
references.pmid: 21804596
references.citation: Cancer Res. 2011 Apr 1;71(7):2664-74
references.pmid: 21324923
references.citation: J Exp Med. 2000 Jul 3;192(1):117-22
references.pmid: 10880532