Abstract 3545: New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions

Abstract

Abstract Immunotherapy has shown tremendous promise in the treatment of blood cancers; however, treatment typically fails when attempted with solid tumors, such as breast cancer. However, the cases where immunotherapies have been successful in breast cancer, the results have been remarkable: full remission of stage 4 disease has been observed. This highlights the need to elucidate how the tumor microenvironment (TME) fosters a context of molecular crosstalk that is hostile to inflammatory, anti-tumor immunological responses that present a significant roadblock to consistently successful immunotherapy. Aberrant IL-33 present in the TME is believed to be one of these major factors that drives tumor progression via its ligand, ST2, and the subsequent recruitment of IL1RAcP. This activates MyD88 cascades in dysfunctional myeloid immune cells and myeloid derived suppressor cells (MDSCs), eliciting immunosuppression that promotes tumor tolerance and subsequent disease progression. To this end, preventing IL-33/ST2 signaling activation is an attractive target to possibly manipulate immune cells to recognize and mount a response against tumor cells. Our previous work has identified 4 IL1RAcP hotspot residues of interaction between it and the ST2/IL-33 complex: R157, K238, K343, and K346. Here, we designed peptides, which mimic these hotspots and the adjacent residues that interact with the ST2/IL-33 complex. Wild type peptides inhibit trimer formation in vitro as determined by immunoprecipitation and chemical crosslinking experiments. Modifications introduced to increase rigidity and stability increased affinity in vitro and showed inhibition of downstream signaling in reporter gene cell models. Citation Format: Jessica Roman, Rachel Carter, Alessandra Luchini, Lance Liotta, Remi Veneziano, Amanda Haymond. New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3545.