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.

Figure 1

Development of human breast carcinoma is characterized by abundant infiltration of immune cells. Representative sections of normal, premalignant, and malignant human breast tissue stained with hematoxylin and eosin (H&E) (upper panels), and following immunodetection of CD45 (leukocyte common antigen, brown staining). DCIS, ductal carcinoma in situ.

Figure 2

Development of human breast carcinoma is characterized by abundant infiltration of lymphocytes into neoplastic tissue. Representative sections of normal, premalignant, and malignant breast assessed for the presence of CD4⁺ (upper panels) and CD8⁺ (middle panels) T lymphocytes (brown staining in panels), as well as CD20⁺ B lymphocytes (red staining in lower panels), demonstrating the extent of immune-cell infiltration into premalignant and malignant stroma. DCIS, ductal carcinoma in situ.

Figure 3

Contrasting roles of adaptive leukocytes during cancer development. During acute inflammatory responses (left panel), Th1 CD4⁺ and CD8⁺ T cells directly regulate tumor cell cytotoxicity, while indirectly polarizing innate immune cells toward tumor suppression (such as M1 polarization of tumor-associated macrophages [TAMs]). B-cell-derived factors (immunoglobulins and complement) facilitate recruitment of innate leukocytes and targeted destruction of neoplastic cells. During chronic inflammation, however (right panel), myeloid suppressor cells, Th2 CD4⁺ T cells and regulatory T (T-reg) cells function in combination to both repress CD8⁺ cytotoxicity and to induce protumoral polarization of innate immune response (such as M2 polarization of TAMs) via cytokine secretion (IL-4, IL-13, IL-10, IL-6 and transforming growth factor beta (TGFβ)). Chronically activated B cells promote accumulation of innate cells in the neoplastic stroma by immunoglobulin and cytokine production. When polarized, as during chronic inflammation, these innate immune cells in turn provide a rich proangiogenic and protumoral microenvironment. CTL, cytotoxic T lymphocyte; FcR, Fc receptor; INF, interferon; SC, suppressor cells; VEGF, vascular endothelial growth factor.

Figure 4

Model depicting the consequences of acute inflammation versus chronic inflammation. During acute antitumor inflammatory responses (left panel), Th1-polarized T cells secrete antitumor cytokines (IL-2 and INFγ, for example), which in combination with antitumor-directed B-cell-derived factors (such as immunoglobulins (Igs)) activate tumor inhibitory responses in recruited innate immune cells and cytotoxic T lymophocytes (CTLs) that together favor tumor rejection. In contrast, chronic activation of immune response (right panel) without resolution (of damage) often results in accumulation of regulatory T (Treg) cells, Th2 cells, and activated B cells, which in turn secrete progrowth factors (IL-4, IL-6, IL-10, IL-13, transforming growth factor beta (TGFβ) and immunoglobulins, for example) that enhance protumor responses in innate immune cells and inactivate CTL cytotoxicity, thus favoring tumor promotion.