Toll-like receptor agonists to the rescue: saving tumor-specific T-cells (101.8)

Abstract

Abstract The molecular basis for the costimulatory effects of toll-like receptor (TLR) agonists are being gradually unravelled, adding to our understanding of how TLR signals enhance T-cell-mediated immune responses. Recent studies indicate that the adjuvant effects of certain TLR agonists may be attributed to activating TLR-myeloid differentiation factor (MyD88) directly in T-cells. We examined the survival of TLR2-MyD88-stimulated CD8 T-cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2 stimulation on pmel CD8 T-cells but not on TLR2-/-pmel or MyD88-/-pmel T-cells enhanced T-cell expansion primarily by reducing apoptosis rather than enhancing cell division. We determined the requirement for intrinsic MyD88 signals within pmel T-cells, by co-transferring congenic MyD88-/-pmel and pmel T-cells into CD45.1 mice and comparing T-cell numbers at different time points. Pmel T-cells outnumbered MyD88-/-pmel T-cells as early as 14 days after adoptive cell transfer and became more disparate after 34 days. MyD88-/- T-cells could not be rescued despite conditions sufficient to support pmel T-cell survival within the same environment. At the molecular level, we detected significant changes in various apoptotic molecules, favoring T-cell longevity. These findings reveal a novel role for TLR-MyD88 signals within tumor-specific T-cells which may inspire new approaches for enhancing cancer immunotherapies by manipulating TLR-MyD88 signaling within T-cells.