A superagonist variant of peptide MART1/melan A(27-35) elicits anti-melanoma CD8(+) T cells with enhanced functional characteristics: Implication formore effective immunotherapy

In the present study, me show that a singly substituted peptide derived fro m the epitope MART1(27-35) and containing a Leu in position 1 (LA-GIGILTV; ii) behaves as a superagonist by in vitro inducing specific T cells with en hanced immunological functions, 1L-specific CTLs can be raised from periphe ral blood of HLA-A2(+) melanoma patients more efficiently than T cells spec ific for the cognate peptide. These T cells show a greater sensitivity to n ative MARTI,,, when compared with CTL variable raised to parental peptide f rom the same patients, More importantly, anti-ii but not anti-native T cell s display high levels of interferon gamma production at early time points, and readily secreted interleukin-2 in response to native epitope endogenous ly presented by melanoma cells. Additionally, anti-ii T cells are insensiti ve to the inhibitory effects of MART1(27-35) natural analogues that antagon ize the lytic response of CTLs raised to the cognate peptide. Analysis of T -cell receptor variable beta usage suggests that the native and ii peptides stimulate different components of the MART1(27-35)-reactive T cell populat ion. These data provide rationale to the use of superagonist analogues of t umor antigens for inducing in vivo immunization potentially able to overcom e tumor immune escape and mediate a more significant control of tumor growt h.