Abstract 4994: Hypoxia-induced autophagy and TNF-alpha resistance in breast cancer cells leads to tumor evasion from NK-mediated immunosurveillance by downregulation of ICAM1.

Abstract

Abstract The major obstacle for defining efficient immunotherapeutic approaches for the treatment of solid tumor is the capability of tumor cells to evade host immune response under hypoxic microenvironment. We have investigated how breast cancer cells manage to evade effective immunosurveillance. Since the host's immune evasion of many breast cancer cells is correlated with the acquisition of resistance to TNF-α, we used TNF-sensitive (MCF-7) and TNF-resistant (1001) breast cancer cells. We showed that the acquisition of TNF resistance in 1001 cells is correlated with the induction of hypoxia inducible factor (HIF)-1α and a constitutive activation of autophagy. When cultured under hypoxia, TNF-sensitive tumor cells activate autophagy and resist to the cytotoxic effect of TNF-α. This data strongly argue for a role of hypoxia in the development of TNF-resistant tumor cell population. Furthermore, we showed that TNF-resistant cells evade natural killer (NK) cells-mediated lysis by a mechanism involving a decrease in the conjugate formation between TNF-resistant and NK cells. The decrease in the ability of NK cells to recognize TNF-resistant tumor cells is related to a dramatic down-regulation of Intercellular Cell Adhesion Molecule (ICAM-1) at the surface of tumor cells. The mechanism responsible for the decrease of ICAM-1 expression in TNF-resistant cells and its functional link with autophagy is currently under investigation. Together, this study discloses the major role of hypoxic microenvironment in the activation of the autophagic process in tumor cells which ultimately leads to tumor evasion from immunosurveillance. Citation Format: Bassam Janji, Joanna Baginska, Sandrine Medves, Kris Van Moer, Salem Chouaib, Guy Berchem. Hypoxia-induced autophagy and TNF-alpha resistance in breast cancer cells leads to tumor evasion from NK-mediated immunosurveillance by downregulation of ICAM1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2013-4994 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.