Amplifying TLR-MyD88 signals within tumor-specific T cells enhances antitumor activity to suboptimal levels of weakly immunogenic tumor antigens.
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.
Geng
Degui
D
University of Maryland Greenebaum Cancer Center and Department of Otorhinolaryngology, Baltimore, Maryland 21201-1559, USA.
Zheng
Liqin
L
Srivastava
Ratika
R
Velasco-Gonzalez
Cruz
C
Riker
Adam
A
Markovic
Svetomir N
SN
Davila
Eduardo
E
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*
D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2
J Immunol. 2000 Jul 1;165(1):539-47
10861094
Blood. 2008 Mar 1;111(5):2704-13
18086870
Arthritis Res Ther. 2004;6(5):R433-46
15380043
J Exp Med. 1978 Sep 1;148(3):799-804
308987
J Clin Invest. 2007 Aug;117(8):2197-204
17657310
J Immunol. 2009 May 15;182(10):6278-86
19414781
Arthritis Rheum. 2000 Mar;43(3):593-8
10728753
J Immunol. 2008 Sep 15;181(6):3804-10
18768833
Eur J Immunol. 1999 Apr;29(4):1209-18
10229088
J Exp Med. 1986 Nov 1;164(5):1652-66
2945892
J Gen Virol. 2009 Feb;90(Pt 2):423-431
19141452
J Biol Chem. 2002 Apr 26;277(17):15028-34
11836257
J Exp Med. 2007 Feb 19;204(2):299-309
17261633
Immunol Lett. 2003 Jan 22;85(2):85-95
12527213
Immunity. 2006 Nov;25(5):783-93
17055754
J Immunol. 1998 Jan 15;160(2):643-51
9551898
FASEB J. 2008 Oct;22(10):3628-37
18587008
J Exp Med. 2005 Oct 3;202(7):907-12
16203864
Proc Natl Acad Sci U S A. 1978 Jan;75(1):436-40
272660
Annu Rev Immunol. 1994;12:337-65
8011285
FASEB J. 2003 Aug;17(11):1567-9
12824285
Eur J Immunol. 2000 May;30(5):1458-68
10820394
J Immunol. 2005 Aug 1;175(3):1551-7
16034093
J Biol Chem. 2006 Apr 7;281(14):9049-57
16455646
Int J Cancer. 1992 Jan 21;50(2):289-97
1730522
J Endotoxin Res. 2000;6(5):411-5
11521065
Eur J Immunol. 2009 Oct;39(10):2673-81
19634192
Am J Physiol Cell Physiol. 2006 Mar;290(3):C917-24
16267105
Nat Rev Immunol. 2004 Nov;4(11):900-11
15516969
J Immunol. 2004 May 15;172(10):6065-73
15128790
J Exp Med. 1998 Jul 20;188(2):277-86
9670040
Cancer Res. 2005 Mar 1;65(5):2001-8
15753400
J Immunol. 2005 Nov 1;175(9):6169-76
16237114
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17469-74
19805141
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3029-34
14981245
J Exp Med. 2004 Mar 15;199(6):775-84
15007094
Eur J Immunol. 2006 Jul;36(7):1684-93
16761317