Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Costimulatory System
Abstract
Costimulatory (CD28, ICOS) and inhibitory (CTLA4, PD-1) molecules of the CD28 receptor family provide critical secondary signals regulating the balance between protective immunity and tissue injury. We recently cloned B- and T-lymphocyte attenuator (BTLA), the third inhibitory receptor of the CD28 family expressed on lymphocytes. Using BTLA-deficient mice and monoclonal antibodies specific for BTLA that we generated, we have studied several in vivo models of infection and autoimmunity, showing the importance of BTLA in regulating immune responses. The hypothesis of this application was that BTLA contributes to the inhibition of breast cancer immunosurveillance, and selective targeting of the BTLA-LIGHT-HVEM costimulatory system can enhance breast cancer immunity. The overall aim was to evaluate the role of BTLA in breast cancer immunosurveillance, and develop novel therapeutics targeting the BTLA-LIGHT-HVEM costimulatory system. We observed that (1) various HVEM mutants were generated that ablate binding of BTLA but preserve binding of LIGHT. However, wild type HVEM but not mutant HVEM is an effective molecular adjuvant in the context of DNA vaccination, (2) expression of BTLA in human breast cancers of various histologic types is restricted to only 1-3% of CD8 T cells in tumor and tumor-draining lymph nodes, (3) in a murine graft-versus-host disease (GVHD) model anti-BTLA therapy permanently prevented GVHD through blockade of alloreactive donor T cells, and, (4) BTLA is highly expressed on a subset of dendritic cells uniquely qualified for cross-presentation of antigen and generation of effective T cell immunity. In summary, progress has been made towards the goal of defining the role of BTLA in breast cancer immunosurveillance.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2012
- Accession Number
- ADA570543
Entities
People
- William Gillanders
Organizations
- Saint Louis University