Circulating inflammatory cells in patients with metastatic breast cancer: Implications for treatment

Abstract

Adaptive and innate immune cells play a crucial role as regulators of cancer development. Inflammatory cells in blood flow seem to be involved in pro-tumor activities and contribute to breast cancer progression. Circulating lymphocyte ratios such as the platelet-lymphocytes ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the neutrophil-lymphocyte ratio (NLR) are new reproducible, routinely feasible and cheap biomarkers of immune response. These indexes have been correlated to prognosis in many solid tumors and there is growing evidence on their clinical applicability as independent prognostic markers also for breast cancer. In this review we give an overview of the possible value of lymphocytic indexes in advanced breast cancer prognosis and prediction of outcome. Furthermore, targeting the immune system appear to be a promising therapeutic strategy for breast cancer, especially macrophage-targeted therapies. Herein we present an overview of the ongoing clinical trials testing systemic inflammatory cells as therapeutic targets in breast cancer.

Keywords: NLR; biomarker; inflammatory cells; macrophages; metastatic breast cancer; new treatments; predictive; prognostic.

Figure 1

Circulating inflammatory cells in blood flow in breast cancer. Inflammatory cells are involved in many ways in promoting cancer cells invasiveness. Evasion of tumor cells from the primary site into circulation is partially permitted by tumor associated macrophages and other immune cell responsible for an immunouppressive microenvironment. Immune cells are also attracted by tumor factors from the blood flows. Circulating tumor cells (CTCs) in blood flow are accompanied in cluster with macrophages and monocytes. Neutrophils release neutrophils extracellular traps (NETs) that determines aggregation of CTCs and other immune cells guaranteeing their survival and a favorable microenvironment in circulation. Platelets, activated by tumor promoting factors, trigger hemostasis mechanisms that catch CTCs cells favoring the adhesion to vessel walls. Lysophosphatidic acid (LPA) dependent mechanism, platelet derived growth factors (PDGFs), interleukin-8 (IL-8) and platelet-derived extracellular vesicles (PEVs) contribute to the formation of platelet clots that include and protect CTCs. CTCs that are not included in aggregates are unlikely to survive in the bloodstream. Immune cells are also important in the formation of the metastatic-niche. Macrophages associated to metastasis (MAMs) derive from the bloodstream and are recruited in the process of metastasis. Adapted from “Breast Cancer to Brain Metastasis”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.

Figure 2

Macrophage-targeted treatment strategies on study. Macrophage-targeted treatment strategies include: inhibition of macrophage and macrophage precursors recruitment targeting the CSF1-CSFR and CCL2-CCR2 pathways, depletion of tumor associated macrophages (TAMs) (like biphosphonates), repolarization of TAMs to an antitumor phenotype, inhibition of tumorigenic factors and mechanisms promoted by TAM and enhancement of macrophage-mediated tumor cell killing or phagocytosis. The repolarization of TAMs is mediated by stimulating the costimulatory receptor CD40, Toll-like receptor 7 (TLR7) or administrating anti-CD47 drugs. Anti CR3 factors enhance the innate activity of macrophages, favoring the antitumoral phenotypes. Ang2 and the respective receptor TIE2 constitute another druggable pathway favoring antitumor responses and inhibiting the functions of TAMs.

Figure 3

CAR-M activity in breast cancer. (A) Macrophages modified with Chimeric antigen receptor (CAR-M) present an improved phagocytic activity and antigen presentation capacity against tumors. CAR-M therapy is developed by the transfer of an edited specific CAR gene into macrophages withdrawn from patient peripheric blood. (B) These genetically modified cells are then more effective in binding to the tumor cell surface via specific antigen identification and active against tumor cells when reinfused into the patient. Furthermore CAR-M are able to produce metalloproteinases (MMPs) that can degrade part of the extracellular matrix (ECM) components in the tumor stroma. This activity facilitate penetration of anti-tumor immune cells into the tumor. Adapted from “Car T Cell Therapy Overview”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.