Bl06ACcl5+/+tnuoc eudon citatsateMDuring the analysis of Runx mutant mouse strains, ****ns3002001007 week-old females13 week-old males***Ccl5ΔPE/ΔPECcl5ΔDE/ΔDECcl5+/+Ccl5ΔPE/ΔPECcl5ΔDE/ΔDEWooseok Seo of the RIKEN Center for Integrative Medical Sciences and his colleagues were intrigued by the unique properties of a chemokine, C-C Motif Chemokine Ligand 5 (CCL5). Chemokines are fundamental regulators of immune cell migration between the bloodstream and tissues; thus, regulating expression of chemokines could augment immune responses in disorders such as cancer. CCL5, also known as RANTES, is a small protein secreted by cells that regulate the immune system. Despite its cru-cial roles in inflammation and cancer immunity, how exactly CCL5 modulates immune responses is not well-understood.Furthermore, CCL5 is produced by both cancer cells (cancer-secreted CCL5) and the immune system (host-derived CCL5), but the latter has been shown to have rather contradictory functions during tumorigenesis and metastasis: it may work as either pro-cancer or anti-cancer depending on circumstances.The RIKEN team addressed these issues by identify-ing two enhancers and demonstrated that expression of Ccl5 (the gene that encodes CCL5) is regulated by each of these enhancers during inflammation and homeostasis phases, respectively, and that these enhancers are further regulated by RUNX/CBFβ complexes and the SATBI chro-matin organizer. A proximal enhancer (located near Ccl5), when combined with transcription factors, increases the production of CCL5 during the steady state. A distal en-hancer further away from Ccl5 induces CCL5 expression in activated immune cells. The team also discovered that the transcription factor RUNX suppresses the function of these two enhancers.Even more striking was the role CCL5 plays in cancer progression. The team injected melanoma cells into nor-mal mice and knockout mice lacking either the proximal enhancer or the distal enhancer.After 14 days, the mice without the proximal enhancer had fewer and smaller tumor cell clusters in their lungs than normal mice (Figure), suggesting that CCL5 produced via the proximal enhancer encouraged tumor cell growth. By contrast, increased CCL5 expression through RUNX3 mutation was associated with more metastatic tumors in the lung. “This indicates that high levels of CCL5 are not good for tumor immunity”, stated principal investigator Ichiro Taniuchi.“The identification of functional enhancers such as these should facilitate the understanding of how other potential regulators might work to activate Ccl5. If we can somehow remove CCL5 from our system, we may actually strengthen our immune system. This could move CCL5 one step closer towards to being an actionable immuno-therapeutic target”, says Seo.Figure: A. Macroscopic images of lungs 14 days after melanoma cells were injected into Ccl5+/+, Ccl5ΔPE/ΔPE and Ccl5ΔDE/ΔDE mice.B. The number of metastatic nodules per mouse (Mean ± SD; ***p < 0.001; ****p < 0.0001; ns non-significant).Original paper:Seo W, Shimizu K, Kojo S, Okeke A, Kohwi-Shigematsu T, Fujii S & Taniuchi I. Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immu-nity. Nature Communications 11, 1562 (2020)Wooseok Seo and Ichiro TaniuchiA curious chemokine, CCL5, paradoxically suppresses the action of immune cells, but RUNX-mediated repression of CCL5 augments immune responses in cancer
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