Abstract
MELOE-1 is an overexpressed melanoma antigen containing a HLA-A2 restricted epitope, involved in melanoma immunosurveillance of patients adoptively transferred with tumour infiltrating lymphocytes (TIL). The use of the full-length antigen (46 aa) for anti-melanoma vaccination could be considered, subject to the presence of Th epitopes all along MELOE-1 sequence. Thus, in this study we evaluated in vitro the immunoprevalence of the different regions of MELOE-1 (i.e. their ability to induce CD4 T cell responses in vitro from PBMC). Stimulation of PBMC from healthy subjects with MELOE-1 induced the amplification of CD4 T cells specific for various regions of the protein in multiple HLA contexts, for each tested donor. We confirmed these results in a panel of melanoma patients, and documented that MELOE-1 specific CD4 T cells, were mainly Th1 cells, presumably favourable to the amplification of CD8 specific T cells. Using autologous DC, we further showed that these class II epitopes could be naturally processed from MELOE-1 whole protein and identified minimal epitopes derived from each region of MELOE-1, and presented in four distinct HLA contexts. In conclusion, vaccination with MELOE-1 whole polypeptide should induce specific Th1 CD4 responses in a majority of melanoma patients, stimulating the amplification of CD8 effector cells, reactive against melanoma cells.
Highlights
IntroductionCTL have been identified as the most powerful effector cells [1]
In antitumor immune responses, CTL have been identified as the most powerful effector cells [1]
Tumour-reactive CD4 T cells have been associated with a good clinical outcome [13], and more recently the same group showed that tumour specific CD4 T cells were present in at least 20% of metastatic melanomas, and suggested that the infusion of tumour infiltrating lymphocytes (TIL) (Tumour Infiltrating Lymphocytes) populations containing CD4 specific T cells could enhance the efficacy of adoptive cell therapy [14]
Summary
CTL have been identified as the most powerful effector cells [1]. The cytokines secreted by CD4+ Th1 cells exert direct antitumor and antiangiogenic effects [10]. It has been demonstrated in a mouse model that only tumour-reactive CD4+ T cells have been found to ensure efficient effector CTLs recruitment at the tumour site [11]. In the same line of thought, it has been demonstrated in a melanoma patient that the adoptive cell transfer of CD4 T cells specific for NYESO-1 antigen induced durable clinical remission and led to endogenous responses against non-targeted tumour antigens, suggesting the stimulation of immune responses by transferred CD4 T cells [15]
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