The yin and yang of leukotriene B4 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.

Keywords: BLT1; BLT2; CD8(+) T cells; Cancer; Immune surveillance; Inflammation; Leukotriene B(4); Neutrophils.

Fig. 1

Yin-yang mechanism of LTB₄-BLT1 axis in control of cancer. LTB₄ is produced from arachidonic acid (AA) through the sequential actions of 5-Lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and Leukotriene A₄ hydrolase (LTA₄H). LTB₄ exerts its biological activities through G-protein coupled receptors, BLT1 (high affinity) and BLT2 (low affinity). BLT1 is expressed on variety of immune cells including granulocytes that mediate tumor promoting inflammation and CTLs that promote immune surveillance leading to anti-tumor immunity. Expression of BLT2 on epithelial cells has been implicated in pro-tumorigenic signaling by promoting chemotherapy resistance, angiogenesis, inflammation and metastasis.

Fig. 2

Crystalline Silica (CS) promotes lung tumor progression through LTB₄-BLT1 pathway. Exposure of CS leads to production of LTB₄ predominantly from mast cells and macrophages. In lung epithelial cells exposure of CS leads to production of CXC chemokines. The sterile inflammation initiated by the mast cell produced LTB₄ is perpetuated by autocrine loop of neutrophil produced LTB₄. CS-induced cell death/phagocytosis loop of macrophages also contributes to production of LTB₄. Altogether, CS-induced LTB₄, IL-1β and CXC chemokines result in increased inflammation and recruitment of tumor promoting N2 neutrophils leading to enhanced tumorigenesis.

Fig. 3

BLT1 influences gut microbiota to regulate colon tumorigenesis. Apc^Min/+ mice develop spontaneous intestinal tumors. Deletion of BLT1 in the Apc^Min/+ background led to defective host response (e.g., decrease in host defense proteins such as angiogenins and Reg3γ) and altered gut microbiota. BLT1^−/−Apc^Min/+ mice displayed a significant increase in highly inflamed rapidly growing colonic tumors. BLT1^−/−Apc^Min/+ mice raised under germ free condition are free of colon tumors that reappeared upon fecal transplantation.

Fig. 4

Expression of BLT1 on CD8⁺ T cells is critical for immune surveillance. Tumor antigens are presented by dendritic cells (DC) to Naïve T cells at the draining lymph nodes (LN). The activated cytotoxic T cells (CTLs) acquire the expression of BLT1 and CXCR3 allowing them to enter the tumors resulting in regression. Absence of either BLT1 or CXCR3 results in failure of CTL migration to tumors leading to unchecked tumor growth and failure of PD1 based immunotherapy.