Abstract 1342: A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells

Abstract

Abstract Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has become clear that in order for immune-based cancer therapy to be successful, the major obstacle of immune tolerance to tumor self-antigen must be overcome. Here we report a strategy to accomplish this by engineering molecular events at the interface between antigen peptide-MHC (pMHC) and TCR. In particular, our approach is based on fusion of pMHC to the protein annexin V (ANXA5), which behaves as a ‘dynamic anchor’. The dynamic anchor, in a synchronized and synergistic manner, couples the early onset of TCR signaling by cognate pMHC with a boost in pMHC-TCR affinity, with serial pMHC binding, and with extensive TCR crosslinking. In our system, the dynamic anchor is linked to pMHC and strongly attaches to the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. This anchor in turn exerts a mechanical force that stabilizes interactions at the pMHC-TCR interface. Furthermore, once the dynamic anchor attaches to these T cells, it facilitates repeated, serial pMHC binding and quickly arranges into uniform 2D matrices, thereby prompting TCR crosslinking. We found that fusion of ANXA5 to pMHC augments activation of cognate T cells by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to a new class of vaccination that can raise a robust immune response against low affinity tumor self-antigen. Citation Format: Chih-Ping Mao, Chien-Fu Hung, TC Wu. A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2015-1342