Dissecting the Mechanism of T Cell Tolerance for More Effective Breast Cancer Vaccine Development
Abstract
T cell tolerance to tumor-associated antigens is a significant barrier to immune based treatments of human cancers. One such tumor-associated antigen is the protooncogene HER-2/neu (neu) which is overexpressed in 35-40% of all human breast cancers. Although patients with neu expressing tumors develop antibody and T cell responses to this antigen, these responses are weak and unable to hinder tumor growth. Our work has focused on understanding these mechanisms of T cell tolerance using the neu-N transgenic mice that express the wild type rat neu cDNA under control of the MMTV promoter. Since neu is an endogenously expressed antigen, profound neu-specific immune tolerance exists in the neu-N mice. We have characterized the immunodominant T cell epitope of neu recognized by parental FVB/N mice, RNEU420-429. Studying T cell responses to this epitope has yielded important insights into the mechanisms of tolerance in the neu-N mice. Following a neu-targeted vaccine, 100% of FVE/N mice will activate T cells specific to RNEU420-429, whereas RNEU420-429-specific T cells are not activated in the neu-N mice. However, if vaccine is combined with immunomodulatory doses of chemotherapy in neu-N mice, RNEU420-420-specific are now activated in a subset of transgenic mice. Employing MHC tetramer technology, adoptive transfer of RNEU420.429-specific T cells, and T cell activation assays, we have begun to understand the mechanisms of tolerance that prevent the induction of protective immunity against tumors in the neu-N mice and ways to circumvent them. These findings are the basis for a Phase I Clinical Trial now underway at our institution.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA435335
Entities
People
- Brian H. Ladle
- Elizabeth M. Jaffee
Organizations
- Johns Hopkins University