Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Costimulatory System

Abstract

Public reporting burden for this c ollection of information is esti mated to average 1 hour per res ponse, including the time for reviewing instruc tions, searching existing data sources, gathering and mai ntaini ng the data needed, and completing and reviewing this collecti on of information. Send c omments regarding this burden esti mate or an y other as pect of this c ollection of information, including suggestions for reducing this burden to Department of Defense, Washi ngton H eadquarters Ser vices, Directorate for Information Operations and R eports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. R espondents should be awar e that notwithstandi ng any other provision of law, no pers on s hall be s ubject to any penalty for failing to c ompl y with a coll ection of infor mati on if it does not di splay a currentl y valid OMB c ontrol number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE May 2012 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS( ES)Washington University AND ADDRESS( ES) PERFORMING ORGANIZATION REPORT NUMBERSaint Louis MO 63130-4862 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS( ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Mat eriel Command Fort Det rick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEM ENTARY NOT ES14. 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 generat...