Abstract B292: HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway.

Abstract

Abstract Modern immune therapies [PD-1/PD-L1 and CTLA-4 checkpoint blockade, adoptive cell transfer (ACT)] have remarkably improved the clinical treatment of metastatic melanoma. These modalities rely on the killing potential of cytotoxic T lymphocytes (CTL) as primary mediator of their anti-melanoma responses. The mechanisms of resistance to and the predominant cytotoxic pathway(s) employed by melanoma-reactive CTLs remain largely elusive. Moreover, strategies to bypass CTL-resistance are urgently needed in clinical melanoma therapy. We hypothesized that down-modulation of death receptors in addition to aberrant apoptotic signaling might confer resistance to death signals delivered by CTLs. To test this hypothesis, we used an in vitro model of resistant sublines generated from MART-1+/A*0201+ parental lines sensitive to MART-1 TCR transgenic CTL (F5 CTL) under serial F5 CTL-selective pressure. Here, we report that F5 CTLs mainly use the TNF-related apoptosis-inducing ligand (TRAIL) cytotoxic pathway, explicitly via DR5, in killing sensitive melanomas. Further, F5 CTL-resistance was due to DR5 down-regulation and abnormal ratio of anti- to pro-apoptotic molecules, both of which were reversed by the FDA-approved epigenetic modifier SAHA. Restoration of sensitivity by SAHA was confirmed using transgenic and patient-derived MART-1-specific CTLs, rhTRAIL and DR5 agonist Drozitumab. Mitochondrial destabilization and cytosolic release of apoptotic molecules was only evident by combination of SAHA and rhTRAIL or Drozitumab. These findings suggest that exposure to SAHA of immune-resistant melanomas can skew towards an intracellular pro-apoptotic milieu, increase death receptor expression, and overcome acquired immune-resistance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B292. Citation Format: Ali R. Jazirehi, Siavash K. Kurdistani, James S. Economou. HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B292.