The immune system and inflammation in breast cancer

Abstract

During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.

Harnessing the immune system for the treatment of breast cancer

“…Forkhead box P3 (FOXP3)-expressing Treg cells are a potent mediator of peripheral immune tolerance and suppress a wide range of immune cells, including CD4 + and CD8 + T cells, NK cells, NKT cells, B cells, and antigen presenting cells, through suppression of target cell activation, proliferation, and effector functions (Shevach, 2009;Sakaguchi et al, 2010;Jiang and Shapiro, 2014). Infiltration of Treg cells into breast cancers has been observed in numerous studies, and the number of Treg cells in the tumor site has been shown to be associated with a worse prognosis (Bates et al, 2006;Bohling and Allison, 2008;Ohara et al, 2009).…”

“…The CD8 + T cell is a major antitumor effector cell in breast cancer (Jiang and Shapiro, 2014). CD8 + T cell infiltration is associated with better overall patient outcomes, independent of other prognostic factors such as tumor grade, lymph node stage, size, vascular invasion, and HER2 status (Mahmoud et al, 2011).…”

“…The interplay between the tumor and the immune system during tumor progression is called immunoediting and comprises three phases: elimination, equilibrium, and escape Vesely et al, 2011). In the elimination and equilibrium phases, tumors can be completely eliminated or kept in a dormant state by tumorinhibiting inflammation, characterized by the production of tumor-inhibiting cytokines and the infiltration of cells of both the innate immune system, such as dendritic cells (DCs) and natural killer (NK) cells, and the adaptive immune system, such as Th1 CD4 + and CD8 + T cells Vesely et al, 2011;Jiang and Shapiro, 2014). On the other hand, in the escape phase, breast tumors often develop multiple mechanisms to evade immunosurveillance.…”

“…On the other hand, in the escape phase, breast tumors often develop multiple mechanisms to evade immunosurveillance. These include the creation of cell autonomous modifications which allow cancer cells to evade antitumor cell-mediated destruction (Shin et al, 2001;Jiang et al, 2006;Ryan et al, 2006), and the induction of an immunosuppressive microenvironment by tumor and/or stromal cells, which diminishes the function of effector cells and directly promotes cancer cell proliferation and migration (Jiang and Shapiro, 2014). Chronic inflammation in the tumor microenvironment and the resulting tumor evasion of the immune system have recently been recognized as another hallmark of cancer (Hanahan and Weinberg, 2011).…”

Intratumoural inflammation and endocrine resistance in breast cancer

“…For example, multiple studies have shown that CD8 C tumor-infiltrating lymphocytes (TIL) are associated with improved outcome in breast cancer (Mahmoud et al 2011, Liu et al 2012, particularly in estrogen-receptor-negative breast cancer where TILs are often present in higher numbers (Teschendorff et al 2007a,b). However, it is increasingly clear that inflammation-associated tumour-promoting mechanisms can also be a factor in breast cancer progression (Baumgarten & Frasor 2012, Coussens et al 2013, Jiang & Shapiro 2014. Perhaps more significant are the results of studies that have indicated that inflammation mediates or modifies the response to treatment , DeNardo et al 2011, West et al 2011, Andre et al 2013.…”