Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression

Abstract

Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response elicited. Acute tumor-directed immune responses involving cytolytic T lymphocytes appear to protect against tumor development, whereas immune responses involving chronic activation of humoral immunity, infiltration by Th2 cells, and protumor-polarized innate inflammatory cells result in the promotion of tumor development and disease progression. Herein we review this body of literature and summarize important new findings revealing the paradoxical role of innate and adaptive leukocytes as regulators of breast carcinogenesis. IntroductionBreast cancer is the most frequent malignant tumor of women in North America [1]. Standard treatment modalities have improved the overall outlook and quality of life for women with breast cancer; however, the fact that 40% still succumb to disease highlights the need for new therapeutic approaches and identification of new therapeutic targets. While genetic and epigenetic changes in genes that regulate mammary epithelial cell proliferation, survival, polarity and/or differentiation are probable 'initiators' of breast carcinogenesis, several lines of evidence indicate that stromal cell responses in premalignant mammary tissue may 'promote' progression to cancer and/or the metastatic capability of malignant mammary epithelial cells. Cellular components of tumor stroma include (myo)fibroblasts, vascular cells, infiltrating leukocytes and specialized mesenchymal support cells unique to each tissue microenvironment. A growing body of evidence has recently implicated tumor-infiltrating leukocytes as causal players in cancer development [2][3][4][5][6][7][8].The present review focuses on the paradoxical roles of innate and adaptive leukocytes as regulators of breast carcinogenesis, and highlights recent experimental data indicating that therapeutically targeting these diverse immune cell types by either neutralizing and/or bolstering their specific bioactivities may provide a therapeutic advantage to patients with breast cancer. Leukocytes and carcinoma development

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

“…57 In the PyMT model, metastatic progression requires CD4 ϩ T helper-2 (Th2, tolerogenic) cells that activate tumor promoting macrophages. 58 A polarized Th1 (cytotoxic) response in T cells activates the M1 macrophage phenotype and immune rejection of tumors.…”

“…58 A polarized Th1 (cytotoxic) response in T cells activates the M1 macrophage phenotype and immune rejection of tumors. 57 Adamts1 Ϫ/Ϫ tumors had increased CD45 ϩ and IL-12 ϩ cell density and elevated mRNA for CD40L (a Th1 co-stimulatory signal), and for SOCS2 and Tbet (signal transduction factors that promote cytotoxic Th1 cell differentiation), as well as elevated expression of IL-12 (a Th1-mediating cytokine) and of the cytolytic enzyme granzyme B. Taken together, these results indicate an enhanced cytotoxic host response in ADAMTS1-deficient tumors, a potential cause of heightened apoptosis and reduced tumor growth and metastasis.…”

Leukocytes in Mammary Development and Cancer

“…Although BrCa has not historically been linked to underlying inflammation or infection, it shows tumor-associated inflammation as defined by infiltration of leukocytes into developing tumors where increases in some immune cell subsets in neoplastic stroma parallels disease progression (de Visser et al 2006;DeNardo and Coussens 2007;DeNardo et al 2009). Breast cancer development in woman is characterized by a significant increase in the presence of both innate and adaptive immune cells, with B and T lymphocytes as well as macrophages representing the most abundant leukocytes present in neoplastic stroma (DeNardo and Coussens 2007) (Fig.…”

Repercussions of Breastfeeding by Diabetic Women for Breast Cancer

“…The balance between a protective cytotoxic response and a harmful response can be regulated systemically by the general immune status of the individual (DeNardo and Coussens, 2007). Comprehensive analysis of immune effector functions at different stages of tumor metastasis is fundamental to the design of effective immune intervention.…”

“…Molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response (DeNardo and Coussens, 2007).…”