Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy

Infiltration of immunosuppressive cells into the breast tumor microenvironments (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic triple-negative breast cancer (TNBC) tumor model limiting adoptive cellular therapy. However, approaches to target these cells specifically in the TME are currently lacking. To overcome this barrier, TNBC polymeric micelles nanoparticles (PMNPs) were used for co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta. The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor altered macrophage polarization, reduced MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the adaptive immune response. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic TNBC tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant-restructured TME has promising potential for future clinical trials and translation for improved outcomes in TNBC patients. ### Competing Interest Statement A.V.K. discloses potential interest in DelAqua Pharmaceuticals Inc., SoftKemo Pharma Corp., and BendaRx Pharma Corp. J.S.S receives research funding from Merck Inc, Carisma Therapeutics, Glaxo Smith Kline and is a compensated consultant for PIQUE Therapeutics. C.M.P is an equity stockholder and consultant of BioClassifier LLC; C.M.P is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay. Additionally, J.S.S. holds intellectual property interests with Tessa Therapeutics for the use of lymphodepletion and CD30.CAR T cells for patients with Hodgkin Lymphoma. He has filed for IP protection for the use of STING agonists to enhance CAR T cell therapy for the treatment of patients with solid tumors.