Abstract IA27: Immunomodulation of breast cancer
Authors: Disis Mary L. 
Published: May 2015

Abstract
Breast cancer is immunogenic and there is significant evidence that as breast cancer develops, tumors elicit an adaptive immune response. T-cells infiltrate most breast cancers and in several studies, the presence of elevated intratumoral CD8+ T-cells or elevated CD8+ T-cells in conjunction with a limited T-regulatory cell infiltration is associated with a favorable prognosis. Moreover, patients with breast cancer have been shown to develop immunity against specific proteins expressed by their tumors. Recent studies demonstrate that the development of humoral immunity directed against tumor associated antigens can be detected prior to a breast cancer diagnosis indicating the ability of the immune system to act as a sensor for exposure to aberrantly expressed proteins.
Cellular immunity, directed against breast cancer antigens and elicited by exposure to malignancy, is present even while the disease progresses. The endogenous breast cancer specific cellular immune response is often of a Type II phenotype eliciting primarily antibody immunity rather than cytotoxic T-cells. Furthermore, type II cytokines secreted by T-cells actively dampen the development of a CD8 T-cell response. Type I cytokines, such as interferon gamma or TNF-alpha, are needed to activate antigen presenting cells allowing the presentation of tumor specific antigens via cross-priming, the primary mechanism by which cancer is recognized by T-cells. Immune cells which secrete Type I cytokines are rarely detected or found only in limited numbers in the tumors of most breast cancer patients.
Several therapeutic modalities are under development and designed to increase or stimulate Type I T-cells capable of homing to breast tumors. Active immunization, targeting specific breast cancer antigens, has been shown to directly modulate the breast cancer microenvironment by enhancing cross-priming resulting in the development of epitope spreading. The identification of developing immunity against multiple tumor antigens during the course of treatment has been associated with a survival benefit after vaccination targeting HER-2/neu (HER2). High levels of vaccine induced Type I HER2 specific T-cells have been shown to be inversely associated with serum TGF-beta levels in patients with advanced stage breast cancer. Significantly increasing the number of Type I T-cells targeting breast cancer, via strategies such as adoptive T-cell therapy, has been associated with a measurable clinical response in advanced stage breast cancer. Ex vivo expansion of HER2 specific Th1 cells, after vaccine priming, and infusion of those cells into patients resulted in a 40% clinical response rate in patients with Stage IV treatment-refractory breast cancer. After infusion of Type I HER2 positive T-cells, responding patients developed multiple clonal CD4+ and CD8+ T-cell populations in their peripheral blood, which may be an indication of epitope spreading. The level of HER2 specific T-cells achieved in vivo and the development of a diversity of clonal T-cells was significantly associated with clinical response.
Although breast cancer specific Type I T-cells may not be found in the malignancy at the time of diagnosis, such cells can be induced. The ability to circumvent the immune suppressive microenvironment opens the door for combination immune based therapies utilizing checkpoint blocking antibodies or specific chemotherapies shown to modulate immune suppression to further enhance the number and function of tumor specific Type I T-cells.
Citation Format: Mary L. Disis. Immunomodulation of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA27.