title: Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nakhlé
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Sundstedt
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Plas
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bauchet
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Pierron
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Luce
authors.initials: L
authors.lastname: Bruetschy
authors.affiliation: Immunology Group, Lund University, Lund, Sweden.
authors.forename: Adnan
authors.initials: A
authors.lastname: Deronic
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Törngren
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Liberg
authors.affiliation: Global Drug Discovery Department, IPSEN Innovation, 91966 Les Ulis, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Schmidlin
authors.affiliation: Active Biotech AB, Lund, Sweden.|Immunology Group, Lund University, Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
keywords: CD206; IL-12; Immune therapy; Macrophage polarization; TAMs; TME; Tasquinimod