IntroductionCirculating monocytes are precursors that can differentiate into a variety of tissue-resident macrophages (M⌽s) or dendritic cells (DCs), and even osteoclasts. 1 M⌽s exhibit a variety of activities, some of which are in opposition (ie, proinflammatory versus anti-inflammatory, immunostimulatory versus immunosuppressive, and tissue destructive versus reconstructive). 1 The functional heterogeneity of M⌽s depends, at least in part, on the local microenvironment. 2,3 In analogy with the Th1/Th2 dichotomy of T-cell responses, M⌽s exposed to IFN␥ or IL-4 have been referred to as M1s or M2s (also called alternatively activated M⌽s), respectively. 4 M1s produce IL-12 and TNF␣ and are potent killers of microorganisms (especially intracellular pathogens) and tumor cells. M2s produce IL-10 but not IL-12, scavenge debris, tune inflammatory responses, and promote humoral immunity and tissue repair. 5 The detection in cancer patients of tumor-specific T cells that kill ex vivo autologous tumor cells demonstrates that numerous tumor-cell types are potentially immunogenic. However, spontaneous clearance of established tumors by immune mechanisms is rare and active antitumor immunotherapy usually has poor clinical efficacy. 6 It is now largely documented that established tumors propagate conditions that favor their immune escape. 6 Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) accumulate at tumor sites and maintain immune tolerance that contributes to defeating tumor immunity. 6,7 TAMs are far more abundant than Tregs and, in various solid tumors, constitute the major components of the leukocyte infiltrate. In most cases, especially breast, prostate, cervical, and ovarian cancers, TAM density is correlated with poor prognosis. [8][9][10] Strong evidence suggests that TAMs also promote cancer progression and metastasis. 8,11,12 TAMs are polarized M2 cells with potent immunosuppressive functions. They have poor antigen-presenting capacity, prevent T-cell activation, and may contribute to suppressing DC functions. 4,13,14 They also promote the recruitment of Tregs and Th2 cells (through CC chemokine ligand 17 [CCL17] and CCL22 secretion) and naive T cells (through CCL18). Naive T-cell activation, in an environment dominated by immature DCs and TAMs, is likely to induce anergy. 10,15 In addition, TAM production of growth and angiogenic factors (ie, vascular endothelial growth factor [VEGF] and platelet-derived endothelial cell growth factor [PDGF]), proteases (ie, matrix metalloproteinase 9 [MMP9]), and chemokines (eg, CCL2) favors tumor-cell proliferation, angiogenesis, dissolution of connective tissues, and metastasis. 8,12,14,16 The origin of TAMs has mostly been studied in mice in terms of precursor recruitment, survival, and proliferation. TAMs derive from circulating monocytes that are recruited into tumors by chemotactic factors, such as monocyte-colony-stimulating factor Submitted February 19, 2007; accepted August 29, 2007. Prepublished online as Blood First Edition paper, September 11, 2...

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

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High concordance rates for HPV-DNA quantification and high/low-risk HPV genotyping in paired urine/cervical samples suggest that urinary HPV DNA testing could be useful for cervical lesion screening.

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