Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
- 29 September 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (19), 7442-7454
- https://doi.org/10.1158/0008-5472.can-10-0247
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. Cancer Res; 70(19); 7442–54. ©2010 AACR.Other Versions
This publication has 39 references indexed in Scilit:
- Adoptively transferred effector cells derived from naïve rather than central memory CD8 + T cells mediate superior antitumor immunityProceedings of the National Academy of Sciences of the United States of America, 2009
- The Adaptor Molecule MyD88 Directly Promotes CD8 T Cell Responses to Vaccinia VirusThe Journal of Immunology, 2009
- Engagement of Toll‐like receptor‐2 on cytotoxic T‐lymphocytes occursin vivoand augments antitumor activityThe FASEB Journal, 2008
- TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elementsBlood, 2008
- Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signalingJCI Insight, 2007
- Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulationThe Journal of Experimental Medicine, 2007
- The Adaptor Molecule MyD88 Activates PI-3 Kinase Signaling in CD4+ T Cells and Enables CpG Oligodeoxynucleotide-Mediated CostimulationImmunity, 2006
- Differential roles of TLR2 and TLR4 in the host response to Gram-negative bacteria: lessons from a lipopolysaccharide-deficient mutant of Neisseria meningitidisInnate Immunity, 2000
- Differential roles of TLR2 and TLR4 in the host response to Gram-negative bacteria: lessons from a lipopolysaccharide-deficient mutant of Neisseria meningitidisInnate Immunity, 2000
- Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritidesArthritis & Rheumatism, 2000