Abstract
Abstract Background: Tumor-associated macrophages (TAMs) are the major part of the tumor microenvironment 1, which are classified as two groups - the tumor-suppressing M1 type and the tumor-supporting M2 type 2. Thus, TAMs could act as a double-edged sword. Reprogramming TAMs from M2 to M1 type would improve the efficacy of anti-tumor therapies 3. TAMs may influence the efficacy of therapeutic anti-tumor antibodies. One of the modes of action of therapeutic antibodies is an antibody-dependent cellular phagocytosis (ADCP) 1. However, it is still controversial whether the status of TAMs influences ADCP response 4,5. Resiquimod (R848) is an agonist for Toll-like receptor 7 and 8 (TLR7/8) that can reprogram TAMs from M2 to M1 6. In this study, we evaluated whether R848-induced M1 type TAMs could enhance ADCP response. Therefore, we encapsulated R848 into liposomes, intending to achieve TAM-specific R848 delivery, TAMs re-education, ADCP improvement, and enhancement of therapeutic efficacy of antibodies. Methods: For ADCP assay, mouse bone marrow derived macrophages (BMDM) were differentiated into M1 and M2 as TAM models. Phagocytosis of EGFP-expressing cancer cells (Raji, A431, and SKBR3) by TAMs was evaluated by FACS. For TAM re-education, M2 TAMs were incubated with R848. Expression level of macrophage markers (CD80 and CD206) was measured by FACS. Biodistribution of liposomal R848 (R848-LPs) in WiDr cell-bearing nude mice was evaluated by in vivo imaging and FACS. In vivo TAM re-education ability, ADCP enhancement ability, and tumor growth inhibition ability of R848-LPs combined with therapeutic antibody were investigated in WiDr cell-bearing nude mice. Results: In vitro ADCP assay showed that M1 macrophages elicited the more efficient ADCP response than M2 macrophages towards Raji, A431, and SKBR3 using Rituximab (α-CD20 antibody), α-EGFR antibody (528), and Trastuzumab (α-HER2 antibody), respectively. Upon treatment with R848-LPs, macrophages showed an M1 polarization and an enhanced ADCP response in vitro. In vivo imaging and FACS analysis showed that R848-LPs rapidly accumulated in TAMs at tumor site. R848-LP treatment efficiently enhanced the ADCP response towards WiDr using α-EGFR antibody (528). By the treatment of R848-LPs, a significant increased ratio of CD80/CD206 was observed. WiDr-bearing nude mice treated with R848-LP combined with α-EGFR antibody (528) suppressed tumor growth compared with control groups (non-treatment and α-EGFR antibody without R848-LPs). Conclusions: Liposomal R848 is a potential TAM re-education agent, which could significantly enhance the therapeutic effect of antibodies by improving ADCP. Keywords: tumor-associated macrophage; therapeutic antibodies; antibody-dependent cellular phagocytosis; Resiquimod; liposomes
Published Version
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