TLR Agonist Nano Immune Therapy Clears Peritoneal and Systemic Ovarian Cancer
Ben Marwedel, Henning De May, Lauren Anderson, Lorél Y. Medina, Ellie Kennedy,
Erica Flores, John O’Rourke, Marian Olewine, Irina Lagutina, Lillian Fitzpatrick,
Fred Shultz, Donna F. Kusewitt, Eric Bartee, Sarah Adams, Achraf Noureddine,
and Rita E. Serda*
Intraperitoneal (IP) administration of immunogenic mesoporous silica nanoparticles (iMSN) in a mouse model of metastatic ovarian cancer promotes the development of tumor-specific CD8+ T cells and protective immunity. IP delivery of iMSN functionalized with the Toll-like receptor (TLR) agonists polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA) stimulated rapid uptake by all peritoneal myeloid subsets. Myeloid cells quickly transported iMSN to milky spots and fat-associated lymphoid clusters (FALCs) present in tumor-burdened adipose tissues, leading to a reduction in suppressive T cells and an increase in activated memory T cells. Two doses of iMSN cleared or reduced ovarian and colorectal cancer and protected against future tumor engraftment. In contrast, subcutaneous (SC) and intravenous (IV) delivery of iMSN were without therapeutic effect in mice with peritoneal metastases, supporting the need for activation of regional immune cells. Remarkably, intraperitoneal delivery of iMSN cleared subcutaneously implanted ovarian cancer, supporting homing of antigen specific T cells to extraperitoneal tumor sites.