Abstract 3823: Platinum anti-cancer drugs attenuate T cell-mediated immune suppression through STAT6/PD-L2

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC It has become evident that many immune inhibitory mechanisms in the tumor micro-environment prevent the development of effective T cell responses against the tumor cells in cancer patients. Therapeutic interventions aimed at blocking these pathways have been shown to result in enhanced anti-tumor immunity, but they lack direct cytotoxic effects. Cancer chemotherapeutic drugs have these direct cytotoxic anti-tumor effects and although for some anti-cancer drugs indirect activation of the immune system via induction of an immunogenic type of tumor cell death has been described, their effect on inhibitory pathways in anti-tumor immunity is unknown. We investigated the effect of a wide array of chemotherapeutics on dendritic cell (DC) function and on tumor cell immunogenicity. Using allogeneic and antigen-specific in vitro models, we found that when DCs were matured/activated in the presence of platinum-based chemotherapy, they showed strongly enhanced T cell stimulatory capacity. Programmed death receptor-ligand 2 (PD-L2) expression by DC was markedly reduced upon platinum exposure. The enhanced T cell stimulatory capacity by DC upon platinum exposure was abrogated in the presence of PD-L2 blocking antibodies. This was also observed when the regulator of PD-L2 expression, signal transducer and activator of transcription 6 (Stat6), was knocked down using siRNA. In addition, we found that STAT6 was dephosphorylated in tumor cells by platinum compounds, leading to marked downregulation of PD-L2, resulting in enhanced recognition by tumor-specific T cells. In line with these in vitro findings, we found enhanced Th1 cytokine secretion and T cell proliferative responses in cancer patients upon treatment with platinum-based chemotherapy, confirming the in vivo occurrence of platinum-induced immune deviation. Our findings show that treatment with platinum compounds not only results in enhanced T cell stimulation by DC, but at the same time enhances the sensitivity of the tumor for lysis by cytotoxic T cells. This novel double action of platinum compounds may initiate combinations with other immune stimulatory compounds to increase clinical efficacy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3823.