Cancer-inspired, chimeric microparticles drive differential modulation of bone marrow-derived dendritic cells and...

One major mechanism of solid cancer immunoevasion is the maintenance of a "cold" tumor microenvironment (TME) which acts to suppress and inhibit effector functions of tumor-infiltrating immune cells. Due to their rapid growth, cancer cells have increased metabolic demands which result in accumulation of cancer-associated metabolites within the local microenvironment. These metabolites not only serve to sustain tumor cells but also exert direct immunosuppressive effects on local immune cells. Here, we sought to reverse engineer these TME-derived metabolites as potential, novel treatments for autoimmune disease. We hypothesized that using TME metabolites to synthesize polymers and subsequent polymeric microparticle (MP) fabrication would yield MPs with innate immunomodulatory ability. Additionally, we hypothesized that because these metabolites are all elevated within the TME, combining TME-derived polymers to fabricate 'chimeric' MPs may yield synergistic regulatory effects that could be applied to the treatment of autoimmunity. A literature search yielded 4 promising TME-derived metabolite candidates: lactate, tryptophan, succinate, and α-ketoglutarate. In this study, we synthesized poly-lactate (PLA), poly-tryptophan (PTRY), polyethylene glycol succinate (PES), and polyethylene glycol 2-ketoglutarate (PEKG) for fabrication of homopolymeric MPs. We also fabricated chimeric polymeric MPs consisting of every possible dual combination of each metabolite-based polymer (i.e., PLA+PES, PES+PTRY, PLA+PTRY, PLA+PEKvnG, PES+PEKG, and PTRY+PEKG chimeric MPs). Our results demonstrated that murine bone marrow-derived dendritic cells (BMDCs) treated with these cancer-inspired polymeric MPs retain an immature phenotype denoted by low expression of CD80, CD86, and MHCII and elicited downstream CD4⁺ T cell induction of regulatory T cell phenotypes. Additionally, chimeric MP-treated BMDCs resulted in increased induction of FOXP3⁺CD25⁺ Tregs compared to homopolymeric MP treatment, suggesting that combining TME-derived polymers into chimeric MPs may be synergetic for immunomodulatory function. The early studies on these novel cancer-inspired polymeric MPs demonstrate their potential as 'cargoless' inductors of diverse, immune regulatory responses and, their significant potential for applications in autoimmune and allergic disease therapy.