(602d) Foreign Body Responses Inform Immunotherapeutic Drug Discovery

The foreign body response (FBR) to subcutaneous biomaterial implants involves a complex interplay between inflammatory reactions triggered by the biomaterials and subsequent anti-inflammatory responses aimed at mitigating inflammation. These dynamic interactions strive to establish a balance, thereby preventing tissue damage. Our recent study has uncovered a phenomenon wherein systemic immunosuppression resulting from metastatic cancers or chronic inflammation leads to an abundance of anti-inflammatory immune cells within the biomaterial implants. In response, the FBR triggers overproduction of immunostimulatory biomolecules to partially restore balance. Harnessing these immunostimulatory biomolecules holds promise for developing them into immunotherapeutic drugs that could be administered systemically to counteract disease-induced immunosuppression.

In our investigation, we fabricated porous scaffolds using poly (lactic-co-glycolic acid) (PLGA), an FDA-approved biocompatible polymer, and implanted them subcutaneously in mouse models before disease initiation. These biomaterial implants exhibited vascular ingrowth and were infiltrated by various immune cells, creating an immune niche where pro- and anti-inflammatory cells and biomolecules interacted to achieve a balance. As systemic immunosuppression developed following the progression of metastatic lung cancer or prolonged exposure to lipopolysaccharide (LPS)-induced inflammation, immune cells with anti-inflammatory phenotypes, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), infiltrated the biomaterial implants, as well as major organs like the lungs, spleen, and liver.

However, unlike major organs that eventually succumbed to significant immunosuppression, the biomaterial implants maintained an immune-active environment by overproducing various pro-inflammatory biomolecules due to the FBR. Notably, an overproduction of CXCL1 chemokines within biomaterial implants was consistent across different diseases, suggesting that CXCL1-induced immune stimulation is a common mechanism through which FBR counteracts systemic immunosuppressive signals. CXCL1 chemokines attract immune with pro-inflammatory phenotypes (e.g., neutrophils and macrophages) from the circulation, thereby overriding the dominance of MDSCs and Tregs and mitigating immunosuppression within biomaterial implants.

Further analysis revealed that decorin, an extracellular matrix proteoglycan involved in FBR and a Toll-like receptor 2/4 agonist, increases concomitantly with CXCL1 within biomaterial implants across different contexts of immunosuppression. Upon exposure to decorin, cells derived from major organs experiencing an immunosuppressive environment greatly upregulate CXCL1 production. Meanwhile, multiple immune cells in the major organs shift from anti-inflammatory to pro-inflammatory phenotypes, resulting from the immunostimulatory effects of decorin. Collectively, our study of FBR in the context of disease-induced immunosuppression sheds light on strategies to delivering decorin to major organs, thereby alleviating immunosuppression in situ by promoting CXCL1-induced attraction of pro-inflammatory cells and inducing the phenotypic changes in suppressive immune cells.