Splenic granulopoiesis and S100A9 drive resistance to checkpoint inhibitors conferred by liver metastases

Abstract Here, we investigate why liver metastases reduce the efficacy of immune checkpoint inhibitors (CPI). The poor prognosis of patients with liver metastases is associated with a systemic increase in neutrophils. Using experimental models, we confirm that mice with liver metastases respond poorly to CPI, have elevated neutrophils and suppress the response of subcutaneous lesions to CPI. We demonstrate that liver metastases, acting partly via IL-6, boost granulopoiesis in the spleen and promote the generation of immature S100A9hi neutrophils that suppress T-cell proliferation. Human liver metastases exhibit a similar increase in S100A9hi neutrophils. Neutrophil depletion attenuates the growth of liver metastases, but not subcutaneous metastases. Moreover, genetic deletion of S100A9 enables liver metastases to be effectively treated with CPI, and prevents liver metastases from suppressing the response in subcutaneous metastases. Thus, we document how liver metastases specifically change splenic granulopoiesis leading to changes in the microenvironment of non-hepatic lesions, and how targeting a key neutrophil protein restores the efficacy of CPI. Competing Interest Statement PL Consultant and speakers bureau: BMS, MSD, Pierre Fabre, Novartis, Amgen, Roche, Melagenix, Skyline, MLA Diagnostics. Research funding: BMS, Pierre Fabre. Support for travel: BMS, MSD. Advisory Board Lovance. RL Consultant and speakers bureau: MSD, Pierre Fabre. Research funding: BMS, Pierre Fabre, Astra Zeneca. Advisory board Delcath. ES reports grants from Novartis, Merck Sharp Dohme, AstraZeneca and personal fees from Phenomic.