Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

Abstract

Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors.

Figure 1

Differentiation of tumor-associated myeloid cells begins from hematopoietic stem cells (HSC) in the bone marrow. CMP: common myeloid progenitors, IMC: immature myeloid cells, TEM: Tie2-expressing monocyte, MDSC: myeloid-derived suppressor cell, M-MDSC: myeloid MDSC, G-MDSC: granulocytic MDSC, iDC: immature dendritic cells, TADC: tumor-associated dendritic cells, TAM: tumor-associated macrophage, and TAN: tumor-associated neutrophil [63].

Figure 2

Recruitment pattern of myeloid cells in tumor progression and metastasis. Stages in tumor progression and metastasis including initiation, proliferation and tumor site inflammation, invasion, intravasation, circulation in blood stream, extravasation, and colonization are shown with associated myeloid cells, platelets, and cytokines. The contribution of TAM and TAN at early stage of distant colonization sites is not clear. Green: cytokines/chemokines in recruitment or suppression of immune cells, black: metastasis associated proteins, red arrow: movement of myeloid cells, EMT: epithelial mesenchymal transition, and CTSB: cysteine protease cathepsin B based on [105].

Figure 3

Summary of representative interactions between TAM, TAN, platelet, and tumor cells. The interactions between neutrophil and macrophages have not been significantly understood in the TME and the contribution of platelet in differentiation of TAM and TAN suggested in this review awaits further studies. Tumor cells, blood vessels, and CAF comprise TME. CCL2, CXCL12, CSF-1, SDF-1, complements, and SEMA3A for macrophage recruitment [30, 106]. CSF-1 prompts TAMs to produce EGF. The EGF-CSF-1 loop can be initiated by CAF derived factors, such as CXCL12 and HRGβ1 [106]. IL-4 from CD4+ T cells or tumor cells can activate macrophages to TAMs. CCL18 and osteonectin can increase migration and intravasation of tumor cells in metastasis. CXCL-8, CXCL15, and HMGB1 secreted from tumor cells can recruit TANs in metastatic sites. MPO and cytokines from neutrophil recruit platelet and macrophages. PAR and P2Y receptor are involved in thrombin and ADP mediated platelet activation, respectively. P-selectin is involved in platelet leukocyte tethering and leukocyte activation. α-granule is a storage of proteins that enhance adhesive process, angiogenesis, and extracellular matrix (ECM) degradation [81]. GPIIbIIIa mediates tumor cell and platelet interaction via vWF, fibronectin, and fibrinogen [80]. Red arrow: neutrophil-mediated recruitment of macrophages in tumor. Thick arrow: conversion of platelets, neutrophils, and macrophages to activated platelets, TAN, and TAM, respectively. GPIIbIIIa, glycoprotein IIbIIIa; vWF, Von Willebrand factor; ADP, adenosine diphosphate; PARs, proteinase-activated receptors; P2Y, P2Y receptors; TF, tissue factor; NE, neutrophil elastase; HMGB1, high mobility group protein B1; HRGβ1, heregulin β1.