title: Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.
abstract: The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.
authors: Authors' Affiliations: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and Department of Oncology and Ludwig Center for Cancer Research, University Hospital of Lausanne, Lausanne, Switzerland.
authors: Jaikumar
authors: J
authors: Duraiswamy
authors: Gordon J
authors: GJ
authors: Freeman
authors: George
authors: G
authors: Coukos
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D000077216:Carcinoma, Ovarian Epithelial; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor
references: Annu Rev Immunol. 2008;26:677-704
references: 18173375
references: J Exp Med. 2011 Sep 26;208(10):1949-62
references: 21930770
references: J Clin Invest. 2006 Jul;116(7):1935-45
references: 16778987
references: Int J Cancer. 2010 Aug 15;127(4):759-67
references: 20518016
references: Curr Opin Immunol. 2013 Jun;25(3):381-8
references: 23582509
references: J Clin Invest. 2011 Oct;121(10):4015-29
references: 21911941
references: Semin Oncol. 2010 Oct;37(5):508-16
references: 21074066
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10
references: 18287062
references: Ann Oncol. 2006 May;17 Suppl 5:v181-7
references: 16807453
references: Cancer Res. 2011 Aug 15;71(16):5423-34
references: 21697280
references: Oncogene. 2003 May 19;22(20):3188-92
references: 12789295
references: Cell. 2001 Aug 10;106(3):263-6
references: 11509174
references: Nature. 1998 Mar 19;392(6673):245-52
references: 9521319
references: Cell. 2010 Apr 2;141(1):39-51
references: 20371344
references: N Engl J Med. 2003 Jan 16;348(3):203-13
references: 12529460
references: Expert Rev Anticancer Ther. 2008 Feb;8(2):243-57
references: 18279065
references: Carcinogenesis. 2000 Apr;21(4):585-91
references: 10753190
references: J Immunol. 2005 Aug 15;175(4):2357-65
references: 16081806
references: Int Immunol. 2009 Sep;21(9):1065-77
references: 19651643
references: Blood. 2010 Oct 7;116(14):2484-93
references: 20570856
references: Clin Transl Sci. 2008 Dec;1(3):228-39
references: 20357913
references: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4275-80
references: 20160101
references: Curr Top Microbiol Immunol. 2006;311:155-78
references: 17048708
references: J Exp Med. 2006 Oct 2;203(10):2223-7
references: 17000870
references: Semin Oncol. 2007 Apr;34(2 Suppl 2):S1-15
references: 17512352
references: Nat Med. 2010 Oct;16(10):1147-51
references: 20890291
references: Int Rev Immunol. 2011 Apr-Jun;30(2-3):120-6
references: 21557638
references: Nature. 2011 Jul 13;475(7355):226-30
references: 21753853
references: PLoS One. 2011 Apr 29;6(4):e19499
references: 21559358
references: Ann N Y Acad Sci. 2009 Sep;1174:6-17
references: 19769731
references: Cancer Res. 2000 Jun 15;60(12):3239-46
references: 10866317
references: Cancer Res. 2006 Jul 15;66(14):7276-84
references: 16849577
references: Immunity. 2007 Oct;27(4):670-84
references: 17950003
references: Immunol Rev. 2009 May;229(1):192-215
references: 19426223
references: Nat Med. 2004 Sep;10(9):942-9
references: 15322536
references: J Immunol. 2010 Sep 15;185(6):3174-83
references: 20713880
references: Cancer Immunol Immunother. 2009 May;58(5):687-97
references: 18828017
references: Cancer Res. 2013 Jun 15;73(12):3591-603
references: 23633484
references: Oncoimmunology. 2013 Jan 1;2(1):e22664
references: 23482679
references: Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):E2480-9
references: 23610399
references: Mol Cell Biol. 2005 Nov;25(21):9543-53
references: 16227604
references: J Immunol. 2011 Jun 15;186(12):6905-13
references: 21551365
references: Nat Med. 2008 Jan;14(1):28-36
references: 18157142
references: J Immunol. 2004 Jul 15;173(2):945-54
references: 15240681
references: J Exp Med. 1997 Jul 7;186(1):47-55
references: 9206996
references: Cancer Immunol Immunother. 2005 Nov;54(11):1137-42
references: 15877228
references: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5
references: 17360651
references: Cancer J. 2010 Jul-Aug;16(4):348-53
references: 20693846
references: J Exp Med. 2009 Dec 21;206(13):3015-29
references: 20008522
references: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7875-80
references: 20385810
references: J Exp Med. 2012 Mar 12;209(3):495-506
references: 22351930
references: Nat Rev Cancer. 2006 Feb;6(2):146-55
references: 16491074
references: Immunol Rev. 2008 Apr;222:162-79
references: 18364001
references: J Immunol. 2011 Aug 15;187(4):1634-42
references: 21742975
references: Blood. 2009 Jul 23;114(4):835-43
references: 19465690
references: J Exp Med. 2013 Apr 8;210(4):743-55
references: 23547098