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

Abstract

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.

Appendix

Study institutes: Osaka City University, Akita University, Hirosaki University, National Cancer Center Hospital, Hamamatsu University School of Medicine, Yamagata University Faculty of Medicine, Kyoto University, University of Tsukuba, Nara Medical University, Shizuoka General Hospital, University of the Ryukyus, Iwate Medical University, Oita University, Hiroshima University, Shimane University, Kansai Medical University, Osaka University, Kagawa University, University of Yamanashi, Japanese Red Cross Wakayama Medical Center, Kyoto Prefectural University of Medicine, Kobe City Nishi-Kobe Medical Center, Japanese Red Cross Osaka Hospital, Nagoya University, Harasanshin Hospital, Hokkaido University, Japanese Red Cross Otsu Hospital, Kagoshima University, Kyushu University, Shikoku Cancer Center, Tenri Hospital, Hakodate Goryoukaku Hospital, Kitasato University, Kyoto Katsura Hospital, National Hospital Organization Kyoto Medical Center, Kumamoto University, National Hospital Organization Himeji Medical Center, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Toyooka Hospital, Hokkaido Cancer Center, University of Miyazaki, Hitachi General Hospital, The Jikei University Kashiwa Hospital, Shimada Municipal Hospital, Mie University, Yamaguchi University, Ibaraki Prefectural Central Hospital, Kyoto City Hospital, Kochi School of Medicine, Ijinkai Takeda General Hospital, University of Toyama, Otsu City Hospital, Sapporo Medical University, Kansai Electric Power Hospital, Kurume University, Hyogo College of Medicine, Hirakata Kohsai Hospital, Rakuwakai Otowa Memorial Hospital, Jikei University.