TY - JOUR
T1 - A superagonist variant of peptide MART1/melan A27-35 elicits anti- melanoma CD8+ T cells with enhanced functional characteristics
T2 - Implication for more effective immunotherapy
AU - Rivoltini, Licia
AU - Squarcina, Paola
AU - Loftus, Douglas J.
AU - Castelli, Chiara
AU - Tarsini, Paolo
AU - Mazzocchi, Arabella
AU - Rini, Francesca
AU - Viggiano, Vincenzo
AU - Belli, Filiberto
AU - Parmiani, Giorgio
PY - 1999/1/16
Y1 - 1999/1/16
N2 - In the present study, we show that a singly substituted peptide derived from the epitope MART127-35 and containing a Leu in position 1 (LAGIGILTV; 1L) behaves as a superagonist by in vitro inducing specific T cells with enhanced immunological functions. 1L-specific CTLs can be raised from peripheral blood of HLA-A2+ melanoma patients more efficiently than T cells specific for the cognate peptide. These T cells show a greater sensitivity to native MART127-35 when compared with CTL variable raised to parental peptide from the same patients. More importantly, anti-1L but not anti-native T cells display high levels of interferon γ production at early time points, and readily secreted interleukin-2 in response to native epitope endogenously presented by melanoma cells. Additionally, anti-1L T cells are insensitive to the inhibitory effects of MART127-35 natural analogues that antagonize the lytic response of CTLs raised to the cognate peptide. Analysis of T-cell receptor variable β usage suggests that the native and 1L peptides stimulate different components of the MART127-35-reactive T cell population. These data provide rationale to the use of superagonist analogues of tumor antigens for inducing in vivo immunization potentially able to overcome tumor immune escape and mediate a more significant control of tumor growth.
AB - In the present study, we show that a singly substituted peptide derived from the epitope MART127-35 and containing a Leu in position 1 (LAGIGILTV; 1L) behaves as a superagonist by in vitro inducing specific T cells with enhanced immunological functions. 1L-specific CTLs can be raised from peripheral blood of HLA-A2+ melanoma patients more efficiently than T cells specific for the cognate peptide. These T cells show a greater sensitivity to native MART127-35 when compared with CTL variable raised to parental peptide from the same patients. More importantly, anti-1L but not anti-native T cells display high levels of interferon γ production at early time points, and readily secreted interleukin-2 in response to native epitope endogenously presented by melanoma cells. Additionally, anti-1L T cells are insensitive to the inhibitory effects of MART127-35 natural analogues that antagonize the lytic response of CTLs raised to the cognate peptide. Analysis of T-cell receptor variable β usage suggests that the native and 1L peptides stimulate different components of the MART127-35-reactive T cell population. These data provide rationale to the use of superagonist analogues of tumor antigens for inducing in vivo immunization potentially able to overcome tumor immune escape and mediate a more significant control of tumor growth.
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M3 - Article
C2 - 9927036
AN - SCOPUS:0033555613
VL - 59
SP - 301
EP - 306
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 2
ER -