Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF–induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems

Abstract

BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is IntroductionFor many cancers refractory to conventional therapies, genemodified tumor vaccines have emerged as a promising treatment. Among numerous immunostimulatory cytokines used for tumor vaccines, GM-CSF has been the most intensively investigated and widely studied for use in clinical cancer vaccine trials. [1][2][3] Immunization with irradiated tumor cells engineered to secrete GM-CSF stimulates potent tumor-associated antigen (TAA)-specific antitumor immunity in preclinical 4,5 and clinical settings, including solid tumors and acute myeloid leukemia. 6,7 We have recently shown that the GM-CSF gene-transduced murine monocytic leukemia of WEHI3B cells lose their tumorigenicity when subcutaneously administered into wild-type (WT) BALB/c mice. 8 It is thought that the effective induction of antitumor immunity triggered by GM-CSF is mainly the result of augmented processing and presentation of TAAs by dendritic cells (DCs), followed by both CD4 ϩ and CD8 ϩ T-cell responses. 4,9,10 However, the efficacy of this therapy alone is not durable, partially because of its failure to maintain antitumor memory immunity by TAA-primed T cells. Therefore, there is an imminent need for elaborate studies to improve antitumor memory responses generated by GM-CSF genetransduced tumor cells.Leukotriene B4 (LTB4) is known to be an extremely potent lipid inflammatory mediator derived from membrane phospholipids by the sequential actions of 5-lipoxygenase and LTA4 hydrolase. 11 The major activities of LTB4 include the recruitment and activation of myeloid leukocytes, such as neutrophils. 12 Recently, Del Prete et al have reported a novel role of LTB4 in regulating migration of DCs that precede adaptive immune responses. 13 Lipid LTB4 mediates its functions through the G protein-coupled 7 transmembrane domain receptor superfamily, 14 namely, 2 distinct receptors, BLT1 and BLT2. On the other hand, GM-CSF stimulates the production and function of neutrophils, eosinophils, and monocytes, and activate maturation of DCs. 15,16 However, the underlying significance of the LTB4/BLT1 lipid chemo-attractant pathway in the field of tumor immunology, including GM-CSFinduced immunity, remains elusive.In this context, we investigated the influence of the defective LTB4/BLT1 axis on antitumor memory responses induced by subcutaneous administration of WGM cells using WT and BLT1-knockout (KO) mice. Intriguingly, in vivo experiments showed that marked tumor rejection was reproduced only in BLT1-KO mice when WEHI3B cells were subcutaneously inoculated into WT or BLT1-KO mice that had rejected the outgrowth of WGM cells, implying that that the loss of the LTB4/BLT1 signaling may confer effective generation of TAA-specific memory T cells with retained antitumor effects triggered by GM-CSF. Therefore, the current The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indic...

Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors

“…This suggests that BLT1 mediated regulation of CTL infiltration may be important across a variety of immunogenic solid tumor types including cervical cancers, melanoma and breast cancers. Previous studies have reported a pro-tumorigenic role of BLT1-LTB 4 pathway in various tumors types including melanoma (52–56). In contrast, our studies highlight the importance of BLT1 on immune cells (CTLs) in achieving an effective anti-tumor response.…”

“…Moreover, the data presented here suggests that in the absence of BLT1, major CTL chemokine receptors like CXCR3 that have been demonstrated to be indispensable for T cell trafficking at the tumor vasculature (29), cannot achieve optimum CTL infiltration to tumors and anti-tumor immunity. In a GM-CSF gene transduced leukemia model, Yokota et.al showed that BLT1 knockout mice showed similar or better primary and recall immune responses that were attributed to reduced myeloid derived suppressor cell population in the tumors of BLT1 deficient mice and robust CD4 dependent anti-tumor responses(56). The divergence in the results observed herein, may be due to the differences in the mouse strains (BALB/c), tumor model (leukemia) and expression of GM-CSF in the tumor cells (56).…”

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

“…þ T or CD8 þ T cells were depleted by using GK1.5 or 2.43 mAbs, as previously described (8). Briefly, mice received intraperitoneal injections of anti-mouse GK1.5 mAb, anti-mouse 2.43 mAb (50 mg/mouse), or control Ab 6, 4, and 2 days before tumor challenge, and once every 3 days thereafter.…”

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

“…High levels of 5-LO or its metabolites have been observed in various cancers which may directly correlate to the density of tumor infiltrating inflammatory cells [46,47]. Yokota et al found in the absence of LTB 4 /BLT1 signaling, injection of GM-CSF-based tumor vaccine led to rejection of subcutaneous tumors attributed to reduced MDSC recruitment into the tumors [48]. Moreover, a transcriptome analysis of human ovarian carcinoma ascitis indicated that LTB 4 along with other arachidonic acid metabolites PGE2, PGI2 to be associated with early cancer relapse [49].…”

“…CD8 + T cell depletion eliminated these differences indicating that a 5-LO generated mediator, most likely LTB4, facilitates CTL mediated tumor suppression further supporting the above conclusions. In contrast, in a GM-CSF gene transduced leukemia model [48] BLT1 −/− mice showed similar or better primary and recall immune responses that were attributed to a reduced MDSC population in the tumors of BLT1 −/− mice and robust CD4 dependent antitumor responses. The divergence in the results observed between the studies may be due to the differences in the mouse strains (BALB/c), tumor model (leukemia), and expression of GM-CSF in the tumor cells.…”