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bioRxiv · 10.1101/2024.02.14.580378

Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy

LI, C.·Mao, S.·Zhao, H.·He, M.·Wang, M.·Liu, Z.·Wen, H.·Yu, Z.·Wen, B.·Djibo, M.·Tao, J.·Bu, Y.·Gao, W.·Sun, D.
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Abstract

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{gamma} during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3K{gamma} 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{gamma} 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.

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LI, C., Mao, S., Zhao, H., He, M., Wang, M., Liu, Z., Wen, H., Yu, Z., Wen, B., Djibo, M., Tao, J., Bu, Y., Gao, W., Sun, D.. 2024-02-18. Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy. https://doi.org/10.1101/2024.02.14.580378

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