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Supplemental Figure 4: from Cross-talk between 4-1BB and TLR1–TLR2 Signaling in CD8+ T Cells Regulates TLR2′s Costimulatory Effects

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posted on 2023-04-03, 23:06 authored by Ann Mary Joseph, Ratika Srivastava, Jovanny Zabaleta, Eduardo Davila

Co-administration of agonistic 4-1BB antibody and TLR1-TLR2 ligand reduces growth of B16 melanomas in mice.

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University of Maryland, Marlene and Stewart Greenebaum Cancer

National Institute of General Medical Sciences

National Institute on Minority Health and Health Disparities

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ARTICLE ABSTRACT

The activation of TLR-MyD88 (Toll-like receptor-myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1–TLR2-stimulated and unstimulated T-cell receptor transgenic “pmel” and MyD88−/− pmel CD8+ T cells and identified changes in the expression of several TNF family members. In particular, TLR stimulation increased 4-1BB levels in pmel but not in MyD88−/−pmel T cells. A link between 4-1BB and TLR1–TLR2 signaling in CD8+ T cells was highlighted by the suboptimal responses of 4-1BB−/− T cells to TLR1–TLR2 agonist, but their normal response to CD28 or OX40 costimulation. Blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1–TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1–TLR2-stimulated cells were not due to increased mRNA stability nor increased histone activation, but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1–TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1–TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. Cancer Immunol Res; 4(8); 708–16. ©2016 AACR.

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