Dual Targeting of STING and PI3K? Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy [RNA-seq]
The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3K? during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3K? inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3K? to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment. Overall design: B and Bone marrow dendritic cells from KPC mice are harvest and incubate with (MSA2 or MSA2 plus IPI-549) or without treatments. RNA sequencing are conducted to check their differential gene expressions.