PT  - JOURNAL ARTICLE
AU  - Geng, Degui
AU  - Zheng, Liqin
AU  - Srivastava, Ratika
AU  - Velasco-Gonzalez, Cruz
AU  - Riker, Adam
AU  - Markovic, Svetomir N.
AU  - Davila, Eduardo
TI  - Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
AID  - 10.1158/0008-5472.CAN-10-0247
DP  - 2010 Oct 01
TA  - Cancer Research
PG  - 7442--7454
VI  - 70
IP  - 19
4099  - http://cancerres.aacrjournals.org/content/70/19/7442.short
4100  - http://cancerres.aacrjournals.org/content/70/19/7442.full
SO  - Cancer Res2010 Oct 01; 70
AB  - 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. Cancer Res; 70(19); 7442–54. ©2010 AACR.