Harnessing the immune system for the treatment of breast cancer

Abstract

Standard treatment options for breast cancer include surgery, chemotherapy, radiation, and targeted therapies, such as adjuvant hormonal therapy and monoclonal antibodies. Recently, the recognition that chronic inflammation in the tumor microenvironment promotes tumor growth and survival during different stages of breast cancer development has led to the development of novel immunotherapies. Several immunotherapeutic strategies have been studied both preclinically and clinically and already have been shown to enhance the efficacy of conventional treatment modalities. Therefore, therapies targeting the immune system may represent a promising next-generation approach for the treatment of breast cancers. This review will discuss recent findings that elucidate the roles of suppressive immune cells and proinflammatory cytokines and chemokines in the tumor-promoting microenvironment, and the most current immunotherapeutic strategies in breast cancer.

Fig. 1

M2-polarized TAM promotes breast cancer progression, metastasis, treatment resistance and recurrence COX-2 or STAT3 activation polarizes TAM to the M2 phenotype. Expression of microRNA miR-19a-3p in TAM or low dose anti-VEGFR2 treatment polarizes TAM to the M1 phenotype. TAM promotes angiogenesis by producing VEGF, FGF-2, IL-1, and IL-8. TAM also promotes breast cancer cell proliferation by producing EGF, FGF-2, IL-6, TGF-β, and PDGF. In addition, TAM promotes the breast cancer stem cell phenotype by producing EGF, IL-6, and IL-8 or by fusing with breast cancer cells. Lastly, TAM promotes breast cancer cell invasiveness by producing MMPs and EGF. Abbreviations: TAM, tumor-associated macrophage; COX-2, cyclooxygenase 2; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; FGF, fibroblast growth factor; IL, interleukin; TGF, transforming growth factor; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; MMP, matrix metalloproteinase; BCC, breast cancer cell; BCSC, breast cancer stem cell

Fig. 2

Scheme of immunotherapeutic strategies Antitumor immunity can be boosted by antagonizing suppressive factors, such as TGF-β, IL-10, IDO, and PGE2, inhibition of immune checkpoints, and therapeutic vaccines. Proinflammatory mediators, such as IL-6, IL-8, IL-1, TNF-α, CCL5, CCL2, CXCL10 and CXCL12, can also be targeted. Moreover, depleting or reprogramming suppressive immune cells, such as Treg cells, TAM, or B cells, can also indirectly boost antitumor immunity. Immunotherapy combined with conventional therapies will likely improve the overall therapeutic efficacy. Abbreviations: TGF, transforming growth factor; IL, interleukin; PG, prostaglandin; IDO, indoleamine-pyrrole 2,3-dioxygenase; TNF, tumor necrosis factor; CXCL, chemokine (C-X-C motif) ligand; CCL, CC chemokine ligand; CSF, colony stimulating factor; COX-2, cyclooxygenase-2; STAT3, signal transducer and activator of transcription 3

Fig. 3

Dr. Xinguo JIANG