title: Amplifying TLR-MyD88 signals within tumor-specific T cells enhances antitumor activity to suboptimal levels of weakly immunogenic tumor antigens.
abstract: The efficacy of T cell-based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88-stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88(-/-) mice treated with TLR2 ligand and pmel T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88-stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes.
authors.affiliation: University of Maryland Greenebaum Cancer Center and Department of Otorhinolaryngology, Baltimore, Maryland 21201-1559, USA.
authors.forename: Degui
authors.initials: D
authors.lastname: Geng
authors.forename: Liqin
authors.initials: L
authors.lastname: Zheng
authors.forename: Ratika
authors.initials: R
authors.lastname: Srivastava
authors.forename: Cruz
authors.initials: C
authors.lastname: Velasco-Gonzalez
authors.forename: Adam
authors.initials: A
authors.lastname: Riker
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D013945:Thymoma / Q000276:immunology / Q000628:therapy; D051195:Toll-Like Receptor 2 / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2
references.citation: J Immunol. 2000 Jul 1;165(1):539-47
references.pmid: 10861094
references.citation: Blood. 2008 Mar 1;111(5):2704-13
references.pmid: 18086870
references.citation: Arthritis Res Ther. 2004;6(5):R433-46
references.pmid: 15380043
references.citation: J Exp Med. 1978 Sep 1;148(3):799-804
references.pmid: 308987
references.citation: J Clin Invest. 2007 Aug;117(8):2197-204
references.pmid: 17657310
references.citation: J Immunol. 2009 May 15;182(10):6278-86
references.pmid: 19414781
references.citation: Arthritis Rheum. 2000 Mar;43(3):593-8
references.pmid: 10728753
references.citation: J Immunol. 2008 Sep 15;181(6):3804-10
references.pmid: 18768833
references.citation: Eur J Immunol. 1999 Apr;29(4):1209-18
references.pmid: 10229088
references.citation: J Exp Med. 1986 Nov 1;164(5):1652-66
references.pmid: 2945892
references.citation: J Gen Virol. 2009 Feb;90(Pt 2):423-431
references.pmid: 19141452
references.citation: J Biol Chem. 2002 Apr 26;277(17):15028-34
references.pmid: 11836257
references.citation: J Exp Med. 2007 Feb 19;204(2):299-309
references.pmid: 17261633
references.citation: Immunol Lett. 2003 Jan 22;85(2):85-95
references.pmid: 12527213
references.citation: Immunity. 2006 Nov;25(5):783-93
references.pmid: 17055754
references.citation: J Immunol. 1998 Jan 15;160(2):643-51
references.pmid: 9551898
references.citation: FASEB J. 2008 Oct;22(10):3628-37
references.pmid: 18587008
references.citation: J Exp Med. 2005 Oct 3;202(7):907-12
references.pmid: 16203864
references.citation: Proc Natl Acad Sci U S A. 1978 Jan;75(1):436-40
references.pmid: 272660
references.citation: Annu Rev Immunol. 1994;12:337-65
references.pmid: 8011285
references.citation: FASEB J. 2003 Aug;17(11):1567-9
references.pmid: 12824285
references.citation: Eur J Immunol. 2000 May;30(5):1458-68
references.pmid: 10820394
references.citation: J Immunol. 2005 Aug 1;175(3):1551-7
references.pmid: 16034093
references.citation: J Biol Chem. 2006 Apr 7;281(14):9049-57
references.pmid: 16455646
references.citation: Int J Cancer. 1992 Jan 21;50(2):289-97
references.pmid: 1730522
references.citation: J Endotoxin Res. 2000;6(5):411-5
references.pmid: 11521065
references.citation: Eur J Immunol. 2009 Oct;39(10):2673-81
references.pmid: 19634192
references.citation: Am J Physiol Cell Physiol. 2006 Mar;290(3):C917-24
references.pmid: 16267105
references.citation: Nat Rev Immunol. 2004 Nov;4(11):900-11
references.pmid: 15516969
references.citation: J Immunol. 2004 May 15;172(10):6065-73
references.pmid: 15128790
references.citation: J Exp Med. 1998 Jul 20;188(2):277-86
references.pmid: 9670040
references.citation: Cancer Res. 2005 Mar 1;65(5):2001-8
references.pmid: 15753400
references.citation: J Immunol. 2005 Nov 1;175(9):6169-76
references.pmid: 16237114
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17469-74
references.pmid: 19805141
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3029-34
references.pmid: 14981245
references.citation: J Exp Med. 2004 Mar 15;199(6):775-84
references.pmid: 15007094
references.citation: Eur J Immunol. 2006 Jul;36(7):1684-93
references.pmid: 16761317