Degradation-Regulatable Architectured Implantable Macroporous Scaffold for the Spatiotemporal Modulation of Immunosuppressive Microenvironment and Enhanced Combination Cancer Immunotherapy

Abstract

The presence of immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in residual tumors after surgery is known to be related to high recurrence of tumors which are more resistant to therapeutic interventions compared with the primary ones. Herein, a degradation-regulatable architectured implantable macroporous scaffold (Dr-AIMS) is designed to control the immunosuppressive tumor microenvironments (TMEs) as well as to activate T-cell-based antitumor immunity. The Dr-AIMS is fabricated by the combination of stable "bulk" material (methacrylate-modified hyaluronic acid) and hydrolytic-labile "sacrificing" component (methacrylate-modified oxidized hyaluronic acid) with varied blending ratios such that the degradation can be regulated from 10 to 28 days in vivo. The Dr-AIMS is loaded with PTX (depleting cancer cells and TAMs), R837 (activating antigen presenting cells and inhibiting MDSCs functions) and combined immune checkpoint blockade molecules (anti-CTLA-4 and anti-OX40 mAbs, invigorating T cells function) and is implanted as postsurgical treatment in 4T1 breast tumor model. In vivo results suggest the sustained and localized supply of immunomodulatory drugs from Dr-AIMS facilitates the depletion of MDSCs and M2-like macrophages simultaneously within the tumor tissues, enhances the infiltration of DCs and effector T cells into tumor, and systemic antitumor immunity is generated with reduced dose.