The yin and yang of leukotriene B 4 mediated inflammation in cancer

Abstract

The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.

Eicosanoids in Cancer: New Roles in Immunoregulation

“…Several studies have demonstrated that leukotriene production by tumor associated macrophages is critical for T cell recruitment. In particular, LTB4, produced through the actions of 5lipoxygenase and LTA4 hydrolase, has been shown to be a potent chemotactic factor for the recruitment of T cells (Goodarzi et al, 2003;Jala et al, 2017a;Jala et al, 2017b;Tager et al, 2003). While other factors, specifically ligands which bind to CXCR3 on T cells, such as CXCL9 and CXCL10 are critical for T cell recruitment to tumors, deletion of BLT1 and CXCR3 result in equal impairments in T cell recruitment, and the double knockout mice do not show any additivity, suggesting that both of these pathways are required (Chheda et al, 2016).…”

“…Initial studies using 5-lipoxygenase inhibitors, resulted in inhibition of tumor progression (Mohammed et al, 2011). However, more recent studies using mice deficient in expression of the LTB4 receptor BLT-1 (APC min/+ /BLT −/− ), resulted in increased tumor growth, suggesting an inhibitory role for this eicosanoid (Jala et al, 2017a;Jala et al, 2017b). Further, in APC min/+ mice deficient in 5lipoxygenase (APC min/+ /5-LO −/− ) tumor growth was inhibited.…”

Leukotriene receptors as potential therapeutic targets

“…Although the involvement of eicosanoids, especially PGE 2 , in carcinogenesis has been extensively studied (73), the contribution of LTB 4 to cancer has not been well demonstrated. Recently, inflammation has been considered as an important factor in the initiation and progression of certain cancers, and some research has focused on the roles of LTB 4 and BLT 1 in cancer (17). Infection of endothelial cells with Kaposi's sarcoma-associated herpesvirus induced higher expression of 5-LOX, FLAP, and LTA4H, and increased LTB 4 production (74).…”

Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications

“…Hypothesized dominant pathways are shown in heavily-weighted edges. (1,2,(8)(9)(10)(27)(28)(29)31,32,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52) . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”