Peptides Derived from Self-Proteins as Partial Agonists and Antagonists of Human CD8⁺ T-Cell Clones Reactive to Melanoma/Melanocyte Epitope MART1_27–35

Abstract

The self-peptide MART1_27–35 derives from the melanocyte/melanoma protein Melan A/MART1 and is a target epitope of CD8⁺ T cells, commonly recovered from tumor-infiltrating lymphocytes of HLA-A2.1⁺ melanoma patients. Despite their prevalence in such patients, these CTLs generally appear to be ineffective in mediating tumor regression in vivo. We have noted previously that numerous peptides from both endogenous and foreign proteins are similar to MART1_27–35 and, potentially, are capable of productively engaging the T-cell receptors of patient-derived CTLs. This observation raised the question of whether CTLs in vivo might encounter self-peptide analogues of MART1_27–35 that lack full agonist activity, perhaps to the detriment of the antitumor CTL response. This possibility was evaluated using cloned, patient-derived CTLs with a panel of self-derived natural analogues of MART1_27–35 in assays for cytolysis, cytokine release, and phosphorylation of T-cell receptor signaling constituents. Several peptides were identified as partial agonists, capable of eliciting cytolysis and/or release of cytokines tumor necrosis factor-α and IFN-γ but not interleukin 2. Several other peptides showed antagonist behavior, effectively inhibiting cytolysis of MART1_27–35-pulsed targets, but did not inhibit killing of cells prepulsed with a synthetic, heteroclitic variant of MART1_27–35. Some of these antagonists also had lasting effects on interleukin 2 secretion by CTLs under experimental conditions involving sequential exposure to ligands. Together, these observations suggest that encounters with self-peptide analogues of MART1_27–35 may contribute to the peripheral maintenance of these CTLs, while ultimately impairing the efficacy of this antitumor T-cell response.