Effect of quinoline-3-carboxamides on myeloid cells in inflammation and cancer

Sammanfattning: The quinoline-3-carboxamides (Q compounds) are a family of small molecules that ameliorate various types of murine inflammatory autoimmune disease. One such compound has also demonstrated anti-tumor effects in murine tumor models. Several Q compounds have reached clinical trials and one compound, laquinimod, is currently in phase III clinical trial for relapsing-remitting multiple sclerosis. The Q compounds bind to S100A9, which can act as a damage-associated molecular pattern by binding to its receptors TLR4 and RAGE. S100A9 has also been associated with the development of cancer as S100A9 promotes the accumulation and migration of an immunosuppressive myeloid cell population during tumor growth. The aim of this thesis was to investigate the effects of the Q compounds during inflammation and cancer, with particular focus on myeloid cells, in order to better understand the mode of action of these compounds. In the first paper presented, the effect of the Q compound paquinimod was evaluated on myeloid cell accumulation during acute peritonitis. Here, paquinimod specifically reduced the accumulation of inflammatory monocytes and eosinophils in the peritoneum and omentum. These observations were confirmed in subcutaneous matrigel plugs, suggesting that paquinimod may affect the influx of these cells to inflammatory sites. In the second paper, the same cell populations were studied in a mouse mammary carcinoma tumor. Short-term treatment with tasquinimod similarly reduced the recruitment of inflammatory monocytes to tumors. The anti-tumor effect of this compound mainly operated during the first few days of tumor growth and a comparable anti-tumor effect was observed when monocytes were depleted using an anti-Gr1 antibody. In addition, long-term tasquinimod treatment reduced the tumor-induced myeloid cell expansion in the spleen and normalized the changes in the composition of myeloerythroid progenitors in this compartment. In the third paper, the effect of paquinimod was evaluated in a mouse model of spontaneously developed inflammation and fibrosis. Paquinimod reduced the established inflammation in these mice and, remarkably, the fibrosis also regressed. This was associated with a decreased number of M2-polarized macrophages and also NKT cells, which have been shown to be integral for the development of the phenotype in these mice. Paquinimod also dramatically reduced the production of several Th2-associated cytokines by the NKT cells. In summary, the work in this thesis has identified monocytes as one cellular target of the Q compounds. As these cells have important roles in promoting development of inflammatory disease and cancer, these observations may explain the broad effects of the Q compounds observed in various disease models.