The immune contexture in colorectal cancer emerges as an important prognostic factor for patient survival. Accordingly, the relative presence of adaptive immune cell subpopulations in intestinal tumors marks either good prognosis (cytotoxic CD8+ T cells, TH1-polarized CD4+ T cells) or bad prognosis (TH17-polarized CD4+ T cells). Lymphocyte plasticity in colorectal carcinogenesis depends on master inflammatory regulators in myeloid cells such as NF-κB, STAT3 or STAT1, and their downstream mediators, including the cytokines IL-1β, IL-6, IL-23, and TNF-α, which promote, and IL-12 or type I interferons, which restrict carcinogenesis. The production of these cytokines is initially triggered by exogenous or endogenous danger signals. Signaling through pattern recognition receptors recognizing such danger signals receives substantial regulatory input through other signaling pathways. We follow the hypothesis that the sphingolipid sphingosine-1-phosphate (S1P) critically regulates inflammatory cytokines in colorectal cancer by signaling through specific G protein-coupled receptors (S1PRs). Enhanced S1P levels were previously connected to colon carcinogenesis. Own data suggest that particularly S1PR1 and S1PR4 are involved in tumor-associated inflammation. S1PR1 expression in tumor-associated macrophages in mammary carcinoma and fibrosarcoma promoted lymphangiogenesis and metastasis through IL-1β secretion. S1PR4 promoted TH17 development in breast tumors and limited type I interferon production.
Based on this evidence, we propose a tumor-promoting role for S1PR4 and a dominating role of S1PR1 signaling in colorectal cancer metastasis. Specifically, we investigate if S1PR1 expression by macrophages promotes lymph node metastasis via IL-1β in a model of metastatic colon cancer. Additionally we ask whether S1PR4-/- mice show a lower incidence of colitis-associated cancer and analyze the underlying altered cytokine networks and myeloid cell/lymphocyte plasticity. Our studies will identify new regulators of tumor-associated inflammation and may suggest potential pharmacological targets to interfere with inflammatory events that promote colon carcinogenesis and metastasis.
In the lab of Dr. Weigert and Prof. Dr. Brüne Catherine Olesch is working on this project.
Ringleb J, Strack E, Angioni C, Geisslinger G, Steinhilber D, Weigert A, Brüne B: Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages.
J Immunol, 2018, 200:857-868.
Sekar D, Govene L, Del Río ML, Sirait-Fischer E, Fink AF, Brüne B, Rodriguez-Barbosa JI, Weigert A: Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma.
Int J Mol Sci, 2018 19(3). pii: E752.
Weigert A, Strack E, Snodgrass RG, Brüne B: mPGES-1 and ALOX5/-15 in tumor-associated macrophages.
Cancer Metastasis Rev, 2018, 37:317-334.