Clinical and molecular correlates of response to immune checkpoint blockade in urothelial carcinoma with liver metastasis

Despite recent advancements in immunotherapy, urothelial carcinoma patients with liver metastasis have a poor response to immune checkpoint inhibitors (ICIs) and short survival durations. Here, we investigated the clinical activity and molecular correlates of resistance to ICI in patients with metastatic urothelial carcinoma (mUC), focusing on liver metastasis. In this study, 755 patients with mUC who received pembrolizumab (JUOG cohort), 144 mUC patients who were treated with atezolizumab (IMvigor210 cohort), and 59 mUC patients who had metastatic samples available were enrolled. The presence of liver metastasis was associated with increased peripheral monocytes and a reduction in lymphocytes when compared with other metastatic sites, and a poor prognosis for ICI therapy. The peripheral monocyte-to-lymphocyte ratio was significantly correlated with the CD163(+)M2-like tumor-associated macrophage (TAM)/CD8(+) tumor-infiltrative lymphocyte (TIL) ratio in the primary and metastatic UC lesions. Exploratory molecular analyses indicated that ICI-resistant status, such as decreased tumor mutation burden, low CD8(+) TILs and immune checkpoint signatures, and increased M2-like TAM markers, in primary tumors was correlated with the presence of liver metastasis. In metastatic lesions, the CD163(+)M2-like TAM/CD8(+)TIL ratio and expression of cancer-associated fibroblasts induced by the TGF beta signaling pathway were higher in the liver versus the lung metastatic tumors. This study indicated that tumor-infiltrating lymphocyte and macrophage status in primary and metastatic lesions, which correlate with peripheral monocyte and lymphocyte status, may predict immunotherapy outcomes in UC patients with liver metastasis.