S1P receptors shape immune cell plasticity in colorectal carcinoma

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Composition and quality of the tumor-associated immune system in colorectal cancer (CRC) emerged in having both predictive and therapeutic value. Both, lymphocytes and myeloid cells occur in polarized activation states that either restrict or support tumor growth. Lymphocytes such as cytotoxic CD8+ T cells, TH1-polarized CD4+ T cells, memory T cells and myeloid cells such as classically activated macrophages or neutrophils are associated with good patient prognosis, whereas TH17-polarized CD4+ T cells and alternatively activated myeloid cells indicate bad prognosis. Re-activation of anti-tumor lymphocytes with immune checkpoint inhibitors as monotherapy has shown promise in only a subset of CRC patients. Therefore, new targets that shape immune cell plasticity in CRC are needed to polarize the tumor-associated immune system towards tumor rejection. Based on our data generated during the first funding period, we continue investigating sphingosine-1-phosphate (S1P) signaling through S1P receptors 1 and 4 as a driver of immune cell plasticity in CRC. Preventing S1pr1 signaling in myeloid cells restricted development of p53-deficient colorectal tumors in mice, associated with an increase in tumor-associated neutrophils. We follow these observations mechanistically by investigating the contribution of neutrophils to tumor protection upon S1pr1 deletion. Specifically, we analyze the impact of S1pr1 signaling on phenotypic and functional parameters of CRC-associated neutrophils, approach neutrophil depletion in tumor models, and identify mechanisms to explain neutrophil expansion. Deletion of the immune cell-restricted S1pr4 largely prevented CRC growth in the AOM/DSS model without any indication of limited initial inflammation. Rather, S1pr4 deletion, increased protective CD8+ memory T cell infiltrates. Based on RNA-Seq data from CRC-infiltrating CD8+ T cells, we focus on mechanistic analyses towards the contribution of type I interferon signaling to CD8+ memory T cell expansion. Our studies will substantiate findings of the first funding period, suggesting S1P signaling as an important determinant in CRC development by providing S1pr1 and S1pr4-dependent mechanisms of immune cell polarization.