Immunomodulation By Tasquinimod: Skewing Of Tumor Infiltrating Myeloid Cell Populations.

Purpose: Tasquinimod is in phase III development (10TASQ10) for treatment of metastatic castration-resistant prostate cancer. Tasquinimod has shown proof of concept by delaying disease progression and increasing overall survival in a randomized phase II study. Tasquinimod binds to the S100A9 protein and inhibits its interaction with the RAGE and TLR4 receptors, an interaction postulated to be important for the accumulation and function of tumor infiltrating myeloid cells. Treatment with tasquinimod in preclinical tumor models has been shown to result in modulation of immune responses, inhibition of angiogenesis and inhibition of metastasis. Since myeloid cells can contribute to all of the above mentioned areas, we analyzed the effect of tasquinimod on infiltrating cell populations in MC38 adenocarcinoma tumors. Experimental design: Murine colon carcinoma cells (MC38) were inoculated in matrigel in wt or nude C57/Bl6 mice and tumor growth was monitored in the presence or absence of tasquinimod. Effects on vascularization and cell populations were studied by immunohistochemistry on tumors or flow cytometry on isolated cell suspensions. Results: Treatment with tasquinimod inhibited growth of subcutaneously inoculated MC38 tumors. This effect was not restricted to a changed T cell response since tumor growth was also inhibited in nude mice. Treatment effects were associated with a decrease in tumor neovascularization as evident by CD31 immunostaining. A distinct unvascularized necrotic core can be observed in the treated tumors compared to vehicle treated mice. Untreated MC38 tumors showed a substantial infiltration of primarily myeloid cells where most were Ly6ClowCD206+ (M2) macrophages, a population that has been shown to have pro-angiogenic properties. Treatment with tasquinimod led to a reduction in this CD206+ cell population and a concomitant increase in CCR7+ (M1) macrophages. No change was detected in infiltration of CD4+ or CD8+ T cells, including Foxp3+ cells, in accordance with the lack of T cell dependency of tasquinimod effects in this tumor. Conclusions: S100A9 and RAGE has previously been shown to have roles in infiltration of myeloid cells in MC38 tumors. Treatment with tasquinimod, an S100A9-RAGE/TLR4 inhibitor, changes the distribution of myeloid cell populations in the tumor which includes a reduced number of M2 macrophages in the infiltrate. These data suggest that tasquinimod has an effect on tumor infiltrating myeloid cells which could contribute to T cell independent effects on angiogenesis and inhibition of tumor growth. Citation Format: David Liberg, Anders Olsson, Pascale Plas, Marie Torngren, Catherine George, Martin Stenstrom, Fabien Schmidlin, Helena Eriksson, Tomas Leanderson. Immunomodulation by tasquinimod: Skewing of tumor infiltrating myeloid cell populations. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B78.