Myeloid cells in tumor inflammation

Abstract

Bone marrow derived myeloid cells progressively accumulate in tumors, where they establish an inflammatory microenvironment that is favorable for tumor growth and spread. These cells are comprised primarily of monocytic and granulocytic myeloid derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs), which are generally associated with a poor clinical outcome. MDSCs and TAMs promote tumor progression by stimulating immunosuppression, neovascularization, metastasis and resistance to anti-cancer therapy. Strategies to target the tumor-promoting functions of myeloid cells could provide substantial therapeutic benefit to cancer patients.

Figure 1

Mechanisms regulating the recruitment of myeloid cells to the tumor microenvironment. (a) Myeloid cells are activated and mobilized from the bone marrow in response to tumor derived factor such as Bv8, SDF-1α, GM-CSF. (b) Circulating myeloid cells express integrin adhesion molecules in an inactive confirmation, with low binding affinity. (c) In response to diverse chemotactic factors released from the tumor microenvironment, myeloid PI3Kγ activates the adhesion molecule integrin α4β1. (d) Myeloid cells are now able to bind to the activated tumor endothelium expressing the integrin α4β1 ligand VCAM-1. (e) Myeloid cells extravasate from the blood stream and migrate toward the tumor microenvironment, (f) where they differentiate in response to the cytokines/chemokine milieu to tumor associated macrophages. Px, Paxillin; Tn, Talin; TAM, tumor associated macrophages.

Figure 2

Diverse roles of TAMs in the tumor microenvironment. TAMs are critical regulator of tumor initiation and progression. (a) Inflammatory TAMs can initiate a chronic smoldering inflammation that creates a mutagenic and growth-promoting environment. (b) In established tumors, immune suppressive TAMs secrete factors which inhibit the activation of cytotoxic T cells and promotes the recruitment of regulatory T cells. (c) Pro-angiogenic TAMs stimulate the formation of new blood vessels by secreting angiogenic growth factors and ECM remodeling proteases. (d) TAMs support invasion and metastasis of malignant cells by destructing the ECM though proteases, by secreting invasion-inducing factors, and by supporting the establishment of a pro-metastatic niche. ROI, reactive oxygen intermediates; RNI, reactive nitrogen intermediates; ECM, extracellular matrix.