Abstract
BackgroundTasquinimod (a quinoline-3-carboxyamide) is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. Given the major impact of myeloid cells to the tumor microenvironment, manipulation of this cell compartment is a desirable goal in cancer therapeutics.MethodsTo understand the consequences of tasquinimod treatment on the TME, we evaluated early treatment effects in tumor infiltrating myeloid cells. Cellular phenotypes were studied by flow cytometry while gene expression both in tumor tissue and in isolated CD11b+ cells or tumor cells were measured by real time-PCR. Effects on angiogenesis were monitored by changes in CD31 levels and by gene expression in tumor tissue. Effects on cytokine levels in tumor tissue and serum were determined by multiplex analysis.ResultsThe MC38-C215 colon carcinoma tumors showed a substantial infiltration of primarily myeloid cells that were dominated by Ly6ClowF4/80+CD206+ M2-polarized tumor associated macrophages (TAMs), an immuno-suppressive and pro-angiogenic cell population. Here, we show that tasquinimod treatment induces an anti-tumor effect which is subsequent to a reduction in tumor infiltrating CD206+ M2 macrophages and a simultaneous increase in M1 macrophages expressing MHC class II and CD86. The tasquinimod-induced changes in TAM polarization were evident within 24 h of exposure, emphasizing the ability of tasquinimod to rapidly reprogram the tumor microenvironment. This change in the tumor associated myeloid compartment preceded an increased IL12-production within the tumor and a decrease in tumor neovascularization. The switch in TAM polarization by tasquinimod was confirmed in the 4T1 breast cancer model where tasquinimod also reduce lung metastasis development.ConclusionOur data show that tasquinimod affects tumor infiltrating myeloid cells early after exposure, leading to a change in phenotype from pro-angiogenic and immunosuppressive M2-like TAMs to pro-inflammatory M1-like macrophages. These changes are consistent with the effects of tasquinimod seen on tumor vascularization, immune suppression and metastasis giving further insights to the anti-tumor mechanism of action of tasquinimod.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0098-5) contains supplementary material, which is available to authorized users.
Highlights
Tasquinimod is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis
Tasquinimod treatment impairs MC38-C215 tumor growth in vivo Tasquinimod has previously demonstrated potential therapeutic benefit in several xenograft tumor models which has been mainly linked to its anti-angiogenic properties [22]
In a recent study in two different syngeneic tumor models, tasquinimod was shown to modulate myeloid cells, leading to a reduction in tumor immunosuppression and increased efficacy of two different immunotherapies [21]. To further study these changes and to investigate the crosstalk between tasquinimod's immunomodulatory and anti-angiogenic properties, experiments were performed in the MC38C215 tumor model, a variant of the syngenic MC38 colon carcinoma model which has a strong component of tumor associated macrophages (TAMs) with a predominance of the M2-phenotype [32]
Summary
Tasquinimod (a quinoline-3-carboxyamide) is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. The TME contains fibroblasts and endothelial cells and infiltrating lymphocytes and regulatory myeloid cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs). These multiple stromal cells constitute the primary tumorigenic niche and their interactions are critical for tumor growth and metastasis [6]. Polarization seems to depend on the nature of the TME where the localization, type and origin of the tumor, hypoxia, other infiltrating cells, and tumor produced factors is highly associated with the phenotype and function of the infiltrating TAMs [16]. It has been shown that sustained nuclear expression of p50 NFκB homodimer results in a M2 phenotype [17], while by targeting IKKβ and thereby inhibiting NF-κB activity, M2 TAMs could be converted into macrophages of the M1 phenotype [18, 19]
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