Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment

Journal for ImmunoTherapy of Cancer

Tomas Leanderson¹  Fabien Schmidlin²  David Liberg³  Marie Törngren³  Adnan Deronic¹  Luce Bruetschy²  Valérie Pierron²  Anne-Laure Bauchet²  Pascale Plas²  Anette Sundstedt³  Jessica Nakhlé²  Anders Olsson³ 

[1] Immunology Group, Lund University, Lund, Sweden;Global Drug Discovery Department, IPSEN Innovation, Les Ulis, 91966, France;Active Biotech AB, Lund, Sweden

关键词: Immune therapy;    Tasquinimod;    IL-12;    CD206;    Macrophage polarization;    TAMs;    TME;   

Others  :  1234891
DOI  :  10.1186/s40425-015-0098-5

 received in 2015-07-02, accepted in 2015-10-23,  发布年份 2015

【 摘 要 】

Background

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. Given the major impact of myeloid cells to the tumor microenvironment, manipulation of this cell compartment is a desirable goal in cancer therapeutics.

Methods

To 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.

Results

The MC38-C215 colon carcinoma tumors showed a substantial infiltration of primarily myeloid cells that were dominated by Ly6C ^low F4/80 ⁺ 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.

Conclusion

Our 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.

【 授权许可】

   
2015 Olsson et al.

【 图 表 】

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