Altered macrophage differentiation and immune dysfunction in tumor development

Abstract

Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.

Figure 1. Current view of TAM and MDSC differentiation.

HSCs give rise to common myeloid precursors (CMPs), which subsequently originate at least three subsets of cells circulating in tumor-bearing hosts that can be identified by specific markers: monocytes (CD11b⁺Gr-1⁺F4/80⁺), granulocytes (CD11b⁺Gr-1^highF4/80^–IL-4Rα^–), and MDSCs (CD11b⁺Gr-1^medF4/80^low/–IL-4Rα⁺). Circulating monocytes are recruited by tumors and differentiate into TAMs, acquiring protumoral functions. During tumor progression, MDSCs accumulating in blood and in lymphoid organs such as the spleen may also be recruited to the tumor microenvironment, where they become F4/80⁺. This latter pathway of MDSC-TAM phenotype transition (dashed arrow) was recently proposed (13, 27). Finally, it has been hypothesized that immature forms of granulocytes might differentiate into MDSCs or condition their function and/or further differentiation (red arrows), as suggested by some studies (14).

Figure 2. Inhibitory effects of MDSC l-Arg metabolism on antigen-activated T cells.

l-Arg enters MDSCs through a cationic amino acid transporter (CAT-2B) and is mainly metabolized by the inducible forms of NOS and ARG (i.e., NOS2 and ARG1, respectively) although the contribution of other isoforms cannot be ruled out. Depending on the balance between these enzymes, depletion of extracellular l-Arg concentration, NO release, and enhanced production of reactive oxygen and nitrogen species (for example, O₂^– and H₂O₂, and ONOO^–, respectively) can ensue. T cells that are activated in the MDSC-conditioned environment stop proliferating and eventually die by apoptosis through pathways involving activation of general control nonderepressible 2 (GCN2) and soluble guanylate cyclase (sGC); tyrosine nitration and S-cysteine nitrosylation of various proteins; loss of CD3ζ; and interference with the IL-2R signaling pathway (reviewed in ref. 23). cEBP-β, CCAAT enhancer–binding protein β; MSP, macrophage-stimulating protein.

Figure 3. Molecular pathways of macrophage polarization and their role in tumor progression.

The major pathways of macrophage polarization and current evidence linking their activation with either tumor progression (+) or regression (–) are outlined. The overall view suggests that M2 macrophage–polarizing signals (such as IL-10, IL-4, and IL-13) are mainly associated with tumor progression. Contrasting evidence associates M1 macrophage–polarizing pathways (such as IFN-γ and TLR ligation) with either tumor progression or regression. The crosstalk between the M1 and M2 macrophage–polarizing pathways, which results in reciprocal modulation, are also indicated. As shown, IL-10–mediated induction of the p50 NF-κB homodimer interferes with NF-κB activation and M1 macrophage–induced inflammation. The balance between activation of M1 macrophage–associated STAT1 and M2 macrophage–associated STAT3 and STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation results in M1 macrophage polarization, which promotes cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, which is associated with immune suppression and tumor progression. As discussed in the text, IL-23 might also contribute to the polarization decision as it activates different STATs, including STAT1 and STAT3, in TAMs, but direct evidence is missing. CC, colorectal carcinoma; HCC, hepatocarcinoma; Fibr, fibrosarcoma; Mel, melanoma; BC, breast carcinoma; SCC, squamous cell carcinoma; Bl. Carc, bladder carcinoma.