Figure 1.
Tumor epithelial cells induce the expansion, recruitment and differentiation of monocytic and granulocytic cells with distinct ontogenies, plasticities and fates. A simplified diagram of the cellular pathways instructing myeloid cell complicity in cancer is presented.
Expansion: In normal physiology, bone marrow mesenchymal cells express low and localized concentrations of cytokines, including GM-CSF, G-CSF, SCF, and Flt3L, to regulate hematopoiesis (not shown). Carcinoma cells overexpress many of these same factors resulting in elevated and sustained systemic levels and the subsequent expansion of immature myeloid cells. This chronic inflammation induces myeloid cell egress from the bone marrow and extramedullary hematopoiesis. The pleiotropic cytokine, GM-CSF, can signal to myeloid cells at various stages of differentiation with distinct cellular outcomes. GM-CSF induces the proliferation and differentiation of hematopoietic stem cells and their progenitors into MDSC that can accumulate in pathology. G-CSF, another myelopoietic cytokine, promotes granulocyte maturation and can induce the accumulation of Gr-MDSC. GM-CSF and to a lesser extent, G-CSF, can promote Gr-MDSC survival but not proliferation. S100 proteins, VEGF and IL-6 also contribute to MDSC expansion (not shown), perhaps in synergy with GM-CSF.
Recruitment: Solid tumors secrete chemokines that attract myeloid cells. The chemokines CXCL1, CXCL2 and CXCL8 recruit Gr-MDSC. Both normal and tumor epithelium express CCL2 to attract inflammatory monocytes and Mo-MDSC. Inflammatory monocytes give rise to resident monocytes. In cancer, tumor-derived factors can convert normal monocytes into Mo-MDSC or suppressive fibrocytes. Tumors also express CXCL12 to recruit CXCR4+ inflammatory monocytes, Mo-MDSC and fibrocytes. CXCR4 is also expressed on T cells and may inhibit T cell accumulation within the tumor bed (not shown).
Differentiation: After extravasation into normal tissues, monocytes differentiate into macrophages or DC that can either promote immunity or induce T cell tolerance depending on the context. The complex tumor inflammatory milieu instructs myeloid cells to become immunosuppressive Mo-MDSC, macrophages, DC and fibroblasts. Granulocytes and Gr-MDSC may differentiate into neutrophils following extravasation. M-CSF and Th2 cytokines (IL-4, IL13) promote conversion of monocytes into immunosuppressive macrophages; TAM may also be derived from tissue resident macrophages and or resident monocytes. Monocytes can be induced to form regulatory DC by Th2 cytokines or suppressive fibrocytes by TGFβ and PDGF. Fibrocytes may also seed the cancer-associated fibroblast populations with suppressive activity. IFNγ secretion, a hallmark of cytotoxic T cells, also activates a negative-feedback loop that mitigates T cell responses.
Mo-MDSC, monocytic myeloid-derived suppressor cells; Gr-MDSC, granulocytic myeloid-derived suppressor cells; DC, dendritic cell; TAM, tumor-associated macrophage; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; TGFβ, transforming growth factor beta; PGE2, prostaglandin E2; ROS, reactive oxygen species; IDO, indoleamine 2,3-dioxygenase; PDGF, platelet-derived growth factor; iNOS, inducible nitric oxide synthase; PDL2, programmed death ligand 2.