Biodegradable nanoparticles induce cGAS/STING-dependent reprogramming of myeloid cells to promote tumor immunotherapy
Joseph R. Podojil, Andrew C. Cogswell, Ming‐Yi Chiang, Valerie Eaton, Igal Ifergan, Tobias Neef, Dan Xu, Khyati Meghani, Yanni Yu, Sophia M. Orbach, Tushar Murthy, Michael T. Boyne, Adam Elhofy, Lonnie D. Shea, Joshua J. Meeks, Stephen D. Miller
Abstract
Cancer treatment utilizing infusion therapies to enhance the patient’s own immune response against the tumor have shown significant functionality in a small subpopulation of patients. Additionally, advances have been made in the utilization of nanotechnology for the treatment of disease. We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IMPs; named ONP-302) for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.