Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity

• DOI: 10.3389/fonc.2021.644608
• Publication Date: 2021-03-03T05:26:05Z
• Authors: Marina Natoli; Petra Herzig; Elham Pishali Bej...; Melanie Buchi; Reto Ritschard; G. Kenneth Lloyd; Ramon Mohanlal; James R. Tonra; Lan Huang; Viola Heinzelmann; Marta Trüb; Alfred Zippelius; Abhishek S. Kashyap
• Keywords: CD80; CD86; Macrophage polarization

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver 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 immunity. Here, we investigated the effects of plinabulin on macrophage polarization in vitro vivo . Plinabulin monotherapy induced significant growth inhibition mice bearing subcutaneous MC38 colon cancer. Importantly, regressing tumors were characterized by increase M1-like/M2-like tumor-associated macrophages (TAM) ratio. The efficacy remained unaltered T cell-deficient Rag2 −/− mice, suggesting important role driving drug's effect. Exposure murine healthy human toward M1 phenotype, including increased expression co-stimulatory molecules CD80, CD86 cytokines IL-1β, IL-6, IL-12. M2-associated immunosuppressive IL-10 IL-4 reduced. This M1-like skewing TAMs response was dependent JNK pathway. Functionally, plinabulin-polarized directly killed HuT 78 functional as well samples from ovarian cancer patients, preferentially triggering proliferation. Our study uncovers immunomodulatory effect proliferation promoting TAM anti-tumoral effector functions.