Uncovering LAG-3 related tumor immunology in renal cell carcinoma and pan-cancer evaluation.

person Kimiharu Takamatsu Department of Urology, Nerima General Hospital, Tokyo, Japan info_outline Kimiharu Takamatsu, Nobuyuki Tanaka, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya

Authors person Kimiharu Takamatsu Department of Urology, Nerima General Hospital, Tokyo, Japan info_outline Kimiharu Takamatsu, Nobuyuki Tanaka, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya Organizations Department of Urology, Nerima General Hospital, Tokyo, Japan, Department of Urology, Keio University School of Medicine, Tokyo, Japan, Department of Urology, Keio University School of Medicine, Shinjuku-Ku, Japan Abstract Disclosures Research Funding No funding received None. Background: LAG-3 (lymphocyte activation gene 3) is of interest as a target molecule for next-generation immune checkpoint inhibitors in several solid tumors, including renal cell carcinoma (RCC). The aim of this study is uncovering the tumor immune microenvironment (TIME) of the LAG-3-dominant RCC. Methods: Firstly, we performed an automated single-cell count for immunolabelled LAG-3, TIM-3 and TIGIT and TIME evaluation panel molecules (CD3, CD8, CD39, PD1, PDL1, Ctla4, CD68, CD163, CD47, Ki67, CD73, IDO1, GLUT1, CD34 and D2-40) to 105 primary ccRCC tumor samples and created the new classification model. The TIME and clinical value of LAG-3-dominant RCC were evaluated. Secondly, The TIME features of LAG-3 dominant RCC in metastatic sites was evaluated in 47 metastatic samples. Lastly, mRNA seq data from the public cohort and clinical trial data (RCC, n = 1144, other solid cancers, n = 3691) was analyzed with the digital cytometry and evaluated whether the TIME features of LAG-3 dominant RCC are RCC-specific or applicable to other solid tumors. Results: In our cohort and our validated cohort (n = 96), the LAG-3 group had significantly shorter OS (p = 0.037 and p = 0.003). The LAG-3 high expression RCC also showed shorter OS in the TCGA RCC cohort (p = 0.016). As the result of TIME evaluation, LAG-3 dominant RCCs had statistically high level of CD8, high CD39+CD8+, and high M2 macrophages. In metastasis samples, LAG-3 dominant RCCs preserved high level of CD8, high CD39+CD8+. In public mRNA seq analysis, LAG-3 dominant RCCs showed high level of CD8, high CD8+Tregs and high M2 macrophages. High Tregs in LAG-3 dominant tumor were seen in melanoma, HCC and prostate cancer. High M2 macrophage TIME in LAG-3 dominant tumor was unique to RCC, not seen in other solid cancer. Conclusions: LAG-3 dominant RCC had poor prognosis and could exhibit a unique, immunosuppressive TIME.