Abstract 5030: Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages

Abstract

Abstract The M2 phenotype is dominant in tumor associated macrophages (TAMs) and correlates with poor prognosis. As M1 polarized macrophages possess anti-tumor functions, in vivo reprogramming of macrophages is a promising strategy for cancer treatment. We recently demonstrated that microtubule destabilizing chemotherapeutic agents such as plinabulin induce potent dendritic cell maturation and thereby augment anti-tumor immune responses; yet the effects of plinabulin on macrophage polarization remain unknown. Here we demonstrate that plinabulin, which is currently being investigated for both its anti-tumor effect and prevention of chemotherapy-induced neutropenia in phase II/III clinical trials,induces M1 polarization of ex vivo cultured human monocyte-derived M2 macrophages. This was characterized by a reduction in the cell surface expression of M2 markers CD163 and CD206 and an increase in the expression of co-stimulatory M1 markers CD80 and CD86. Phenotypically, plinabulin-polarized human M1 macrophages secreted increasing levels of iNOS and inflammatory cytokines IL-1β, IL-6 and IL-12 while IL-10 and IL-4 secretion decreased. This suggests a functional skewing from immunosuppressive M2 to pro-inflammatory M1 macrophages upon exposure to plinabulin. Similarly, plinabulin induced the M1 polarization of murine FACS sorted F4/80+ intratumoral M2-TAMs, characterized by increased CD80 and decreased CD206 expression. Moreover, systemic treatment (i.p.) of tumor bearing mice with plinabulin led to a significant reduction in the number of tumor-infiltrating TAMs with a concomitant M1 polarization of the remaining TAMs. Indeed, plinabulin treatment of mice bearing subcutaneous MC38 colon cancer or orthotopic EMT6 breast cancer tumors significantly delayed tumor growth. This efficacy of plinabulin remained unaltered in Rag2-/- mice lacking T cells, suggesting that macrophages are required for its anti-tumor activity. These results identify targeting of TAMs by plinabulin as a promising therapeutic strategy. Testing of plinabulin in combination with other macrophage targeting drugs are currently being explored to investigate the dual effect in reprogramming the tumor immune microenvironment. Citation Format: Elham Pishali Bejestani, G. Kenneth Lloyd, Melanie Buchi, Reto Ritschard, Petra Herzig, Ramon Mohanlal, Lan Huang, James R. Tonra, Alfred Zippelius, Abhishek Kashyap. Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5030.