Abstract
High grade gliomas are the most common brain tumors in adult. These tumors are characterized by a high infiltration in microglial cells and macrophages. The immunosuppressive tumor environment is known to orient immune cells toward a pro-tumoral and anti-inflammatory phenotype. Therefore, the current challenge for cancer therapy is to find a way to reorient macrophages toward an antitumoral phenotype. Previously, we demonstrated that macrophages secreted antitumoral factors when they were invalidated for the proprotein converstase 1/3 (PC1/3) and treated with LPS. However, achieving an activation of macrophages via LPS/TLR4/Myd88-dependent pathway appears yet unfeasible in cancer patients. On the contrary, the antitumor drug Paclitaxel is also known to activate the TLR4 MyD88-dependent signaling pathway and mimics LPS action. Therefore, we evaluated if PC1/3 knock-down (KD) macrophages could be activated by Paclitaxel and efficient against glioma. We report here that such a treatment of PC1/3 KD macrophages drove to the overexpression of proteins mainly involved in cytoskeleton rearrangement. In support of this finding, we found that these cells exhibited a Ca2+ increase after Paclitaxel treatment. This is indicative of a possible depolymerization of microtubules and may therefore reflect an activation of inflammatory pathways in macrophages. In such a way, we found that PC1/3 KD macrophages displayed a repression of the anti-inflammatory pathway STAT3 and secreted more pro-inflammatory cytokines. Extracellular vesicles isolated from these PC1/3 KD cells inhibited glioma growth. Finally, the supernatant collected from the coculture between glioma cells and PC1/3 KD macrophages contained more antitumoral factors. These findings unravel the potential value of a new therapeutic strategy combining Paclitaxel and PC1/3 inhibition to switch macrophages toward an antitumoral immunophenotype.
Highlights
Cancer cells share eight common traits (“hallmarks”) that govern their transformation from normal cells and maintenance in the host environment: [1] they stimulate their own growth, [2] they resist inhibitory signals that might otherwise hinder their growth and proliferation, [3] they resist programmed cell death and other cell death mechanisms, [4] they can multiply indefinitely, [5] they stimulate blood vessels growth to supply nutrients to tumors, [6] they invade local tissues and metastasize to distant sites, [7] they have altered metabolic pathways, and [8] they evade the immune system [1]
Considering the above, we recently demonstrated in proprotein convertase proprotein converstase 1/3 (PC1/3) knock-out mice [11], as well as in the pulmonary resident NR8383 rat macrophage PC1/3 knock-down (PC1/3-KD) cell line [12], that PC1/3-deficient macrophages produce high levels of cytokines and chemokines through autocrine and paracrine pathways [13]
We found that PC1/3 KD macrophages displayed a repression of the antiinflammatory pathway signal transducer and activator of transcription 3 (STAT3)
Summary
Cancer cells share eight common traits (“hallmarks”) that govern their transformation from normal cells and maintenance in the host environment: [1] they stimulate their own growth (self-sufficiency in growth signals), [2] they resist inhibitory signals that might otherwise hinder their growth and proliferation (insensitivity to antigrowth signals), [3] they resist programmed cell death (evading apoptosis) and other cell death mechanisms, [4] they can multiply indefinitely (limitless replicative potential), [5] they stimulate blood vessels growth to supply nutrients to tumors (sustained angiogenesis), [6] they invade local tissues and metastasize to distant sites (tissue invasion and metastasis), [7] they have altered metabolic pathways, and [8] they evade the immune system [1]. Elevated systemic or local levels of M-CSF are associated with poor outcomes [7, 9, 10] Taken together, these findings highlight the major roles that TAMs play in mediating tumor growth and metastasis. Considering the above, we recently demonstrated in proprotein convertase PC1/3 knock-out mice [11], as well as in the pulmonary resident NR8383 rat macrophage PC1/3 knock-down (PC1/3-KD) cell line [12], that PC1/3-deficient macrophages produce high levels of cytokines and chemokines through autocrine and paracrine pathways [13] Challenging these cells with endotoxin/LPS, results in a cytokine storm that impacts cell survival of cancer cells [13]. Under LPS stimulation, the TLR4 MyD88-dependent signaling pathway is enhanced in PC1/3deficient macrophages promoting a stable pro-inflammatory activated phenotype Secreted factors from these PC1/3-KD macrophages attract naïve T helper cells and inhibit ovarian and breast cancer cell lines viability via innate immune mechanisms [13]. Because of the key roles of Paclitaxel in microtubule stabilization and tumor resistance, we aimed to study the impact of Paclitaxel on our PC1/3-KD macrophage cell model (Fig. 1A)
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