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 act as a local drug delivery reservoir, modulating the immunosuppressive tumor microenvironment (TME) and activating T-cell-based antitumor immunity as well. The Dr-AIMS is fabricated by the crosslink of methacrylate-modified hyauronic acid under frozen state to form the interconnected macroprorous architacture with pore size of 252.36 ± 59.57 μm. By combining stable “bulk” material (methacrylate-modified hyaluronic acid) and hydrolytic-labile “sacrificing” component (methacrylate-modified oxidized hyaluronic acid) with varied blending ratios, the degradation can be regulated with 10-28 days after implantation in mice. In vitro results indicated that PTX could induce immunogenic 4T1 cell death and deplete TAMs, and R837 could activate antigen presenting cells and inhibit MDSCs functions. After loading PTX, R837 and combined immune checkpoint blockade molecules (anti-CTLA-4 and anti-OX40 mAbs, invigorating T-cells function), Dr-AIMS was implanted as postsurgical treatment (~10% remaining) in 4T1 breast tumor model. In vivo results suggested that the generation of systemic anti-tumor immunity required continuous drug supplies for at least two weeks. The sustained and localized supply of immunomodulatory drugs from Dr-AIMS facilitated the depletion of MDSCs and M2-like macrophages simultaneously within the tumor tissues, converting immunosuppressive TME into antitumor immunity niches. Also, enhanced infiltration of DCs and effector T-cells into tumor was observed, and systemic antitumor immunity was generated with 10-fold reduced doses, resulting in the prolonged survival of mice after surgery of incompletely removed tumor.
Citation Format: Long Ren, Il Woo Shin, Chanyoung Song, Yong Taik Lim. Degradation-regulatable architectured implantable macroporous scaffold for the spatiotemporal modulation of immunosuppressive microenvironment and enhanced combination cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B126.