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

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 S100A9 ^hi neutrophils that suppress T-cell proliferation. Human liver metastases exhibit a similar increase in S100A9 ^hi 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.