Abstract
Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin—a clinical-stage novel agent—modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization in vitro and in vivo. Plinabulin monotherapy induced significant tumor growth inhibition in mice bearing subcutaneous MC38 colon cancer. Importantly, the regressing tumors were characterized by an increase in M1-like/M2-like tumor-associated macrophages (TAM) ratio. The efficacy of plinabulin remained unaltered in T cell-deficient Rag2−/− mice, suggesting an important role of macrophages in driving the drug's anti-tumor effect. Exposure of murine and healthy human macrophages to plinabulin induced polarization toward the M1 phenotype, including increased expression of co-stimulatory molecules CD80, CD86 and pro-inflammatory cytokines IL-1β, IL-6, and IL-12. M2-associated immunosuppressive cytokines IL-10 and IL-4 were reduced. This pro-inflammatory M1-like skewing of TAMs in response to plinabulin was dependent on the JNK pathway. Functionally, plinabulin-polarized human M1 macrophages directly killed HuT 78 tumor cells in vitro. Importantly, plinabulin induced a functional M1-like polarization of tumor infiltrating macrophages in murine tumors as well as in tumor samples from ovarian cancer patients, by preferentially triggering M1 proliferation. Our study uncovers a novel immunomodulatory effect of plinabulin in directly triggering M1 polarization and proliferation as well as promoting TAM anti-tumoral effector functions.
Highlights
Tumor-associated macrophages (TAMs) are predictive of poor prognosis in the majority of advanced tumors and their presence is associated with increased tumor vascularization and resistance to chemotherapy [1]
Given our recent finding that microtubule destabilization triggers the activation of Jun N-terminal kinase (JNK) in murine dendritic cells [14], we investigated the involvement of JNK in plinabulin-induced M1 polarization and proliferation of human macrophages in vitro (Figure 4A)
microtubule-targeting agents (MTAs) plinabulin binds to the colchicine pocket of β-tubulin, in α,β-tubulin heterodimers, at a distinct site and with predicted kinetics that differ from colchicine and other tubulin-targeting agents [18]
Summary
Tumor-associated macrophages (TAMs) are predictive of poor prognosis in the majority of advanced tumors and their presence is associated with increased tumor vascularization and resistance to chemotherapy [1]. TAMs found in most tumors are predominantly of the M2 phenotype, which is associated with tumor-promoting functions and high expression of arginase-1, IL-10, CD163, and CD206 [2]. A higher infiltration of M1 TAMs—defined by high expression of IL-1β, inducible nitric oxide synthase (iNOS), CD80, CD86, and MHC class II molecules—correlates with good outcome in selected cancer types, including non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian and gastric cancers [3]. Alternative therapeutic approaches are aimed at re-programming TAMs by promoting M1 pro-inflammatory and anti-tumoral functions. Agonistic targeting of CD40 leads to TAM-induced remodeling of the extracelluar matrix (ECM) increasing T cell infiltration [10]. Combination of agonistic CD40 antibodies with dual VEGFA/Ang blockade was shown to enhance antitumor responses in vivo, in part by inducing proinflammatory (M1-like) macrophage activation [11]
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