Interferon‐γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor‐associated macrophages

Abstract

Tumor-associated macrophages (TAM) are M2d-polarized cells (IL-10 high , IL-12 low , ILT3 high , CD86 low ) that accumulate in tumor microenvironment. TAM inhibit antitumor T lymphocyte generation and function, contribute to tumor tolerance and are trophic for tumors. In this study, we investigated whether some immunological factors may reverse TAM immunosuppressive properties. Among 32 cytokines, we have identified IFNc on its ability to switch immunosuppressive TAM into immunostimulatory cells. Upon IFNc exposure, TAM purified from ovarian cancer ascites recover a M1 phenotype (IL-10 low , IL-12 high ), express high levels of CD86 and low levels of ILT3, enhance the proliferation of CD4 1 T lymphocytes and potentiate the cytotoxic properties of a MelanA-specific CD8 1 T cell clone. IFNc-treated TAM also secreted reduced levels of mediators promoting suppressive T cell accumulation (CCL18) and trophic for tumors (VEGF and MMP9). As TAM derive from the local differentiation of peripheral blood monocytes, we investigated whether IFNc may also affect TAM generation. In the presence of ovarian ascites, IFNc skewed monocyte differentiation from TAM-like cells to M1-polarized immunostimulatory macrophages. Together, these data show that IFNc overcomes TAM-induced immunosuppression by preventing TAM generation and functions. These data highlight that IFNc used locally at the tumor site could potentiate the efficacy of antitumor immunotherapies based on the generation of effector T cells. ' 2009 UICC

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Production of CCL17, CCL1, chemokine (C-X-C motif) ligand-13 (CXCL13) and CXCL8 (IL-8) has been proven to be associated with an M2a, M2b, M2c and M2d monocyte activation program, respectively, and are parts of mononuclear phagocyte-mediated regulatory circuits of innate and adaptive immunity (Mills et al, 2000;Sironi et al, 2006;Martinez et al, 2008;Duluc et al, 2009;Wang et al, 2010;Zhang et al, 2010a). As shown in Figure 5c, CCL17 levels markedly increased whereas CCL1 did not show apparent change upon M-CSF þ MCP-1, LXA 4 and ANXA1 administration.…”

“…M1 has potent microbicidal properties and promotes Th1 responses, whereas M2 supports Th2-associated effector functions (Mills et al, 2000;Martinez et al, 2008). M2 macrophages are further subdivided into M2a, M2b, M2c and M2d cells as elicited by different stimuli (Sironi et al, 2006;Martinez et al, 2008;Duluc et al, 2009). M2a and M2b macrophages exert immune regulatory functions and drive Th2 responses, whereas M2c macrophages have a predominant role in suppressing immune responses and in promoting tissue remodeling.…”

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

“…The TAM phenotype is reversible and these cells can be re-educated to exert antitumor activity [41][42][43]. In a recent study [44], anti-CD40 antibodies with agonist activity have been shown to have antitumor potential in both murine and human carcinoma of the pancreas.…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…As an example, type I and type II IFNs can revert M2-type macrophages into immunostimulatory cells. 4 To the same extent, GM-CSF prevents the differentiation of human monocytes into immunosuppressive macrophages. 5 At the tumor site, the accumulation of immunosuppressive cells abrogates effector cell functions and contributes to maintain tumor-immune tolerance.…”