Abstract 2547: Peripheral immune signatures and survival in stage IV melanoma

Abstract

Abstract The presence of peripheral T-cells recognizing the melanoma-associated antigens NY-ESO-1 or Melan-A, as well as low frequencies of circulating CD14+ HLA-DR-/low myeloid-derived suppressor cells (MDSCs), is associated with prolonged survival in stage IV melanoma (n=94). In addition, the two of 12 patients with partial responses or stable disease in pilot studies of ipilimumab treatment both tended to have lower levels of MDSCs at baseline which decreased further on treatment. In contrast, two patients with progressive disease had high baseline MDSC levels, which increased further after treatment. These patients are being followed up to determine whether another mechanism of action of ipilimumab may be via an effect on MDSCs. A correlation was observed between the presence of antigen-reactive T cells and the frequency of MDSCs. Our results indicate that patients lacking antigen-reactive T cells had significantly higher levels of MDSCs. In addition, high frequencies of MDSCs correlated with lower frequencies of NY-ESO-1- and Melan-A-reactive T cells that also produced lower levels of IFN-gamma. NY-ESO-1 was recognized more frequently by CD4+ than by CD8+ T cells, whereas Melan-A more often stimulated CD8+ T cells. Possession of NY-ESO-1-reactive T cells conferred a survival advantage whether the response was mediated by CD4+ or CD8+ T cells or both. However, recognition of Melan-A by CD4+ T cells was associated with poorer clinical outcome even when the patient also possessed CD8+ reactive T cells. This negative effect was mediated by CD4+ T cells with a Th2- or Th17-type but not Th1-type cytokine response. Thus, tumor antigen-specificity and function of peripheral T cells and their interactions with MDSCs in advanced melanoma carries significant prognostic weight for predicting survival and may provide mechanistic insights into tumor immunosurveillance in such patients. Citation Format: Graham P. Pawelec, Alexander Martens, Claus Garbe, Benjamin Weide, Evelyna Derhovanessian, Dirk Schadendorf, Anna Maria Di Giacomo, Michele Maio, Jolanda de Vries, Henning Zelba. Peripheral immune signatures and survival in stage IV melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2014-2547