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 TGFβ 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.