Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy

Abstract

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

A comprehensive analysis of the prognostic value and immune infiltration of low expression DBT in clear cell renal cell carcinoma

“…Currently, immunotherapy for tumours focuses on the restoration of the host’s antitumour immune response by blocking immune checkpoints ( Sanmamed and Chen, 2018 ). Blockade strategies targeting the immune checkpoint genes CTLA4 ( Topalian et al, 2016 ; Atkins and Tannir, 2018 ; Braun et al, 2021 ), TIGIT ( Hong et al, 2018 ; Takamatsu et al, 2021 ), LAG3 ( Klümper et al, 2020 ), and PDCD1 ( Sunshine and Taube, 2015 ; Hayashi and Nakagawa, 2020 ) have long been or will soon be effective tools for the treatment of advanced ccRCC. However, DBT was significantly negatively correlated with these molecules, implying that DBT expression might counteract immune escape or immunosuppression in ccRCC to some extent.…”

Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer

“…The tumor center (TC) and invasive margin (IM) of each specimen were selected, with regard to representative areas of the WHO/ISUP grade, and 3 mm tumor cores were punched for sampling. 17 18 In total, 344 cores were acquired and processed for further experiments. All samples were assigned numbers for identification to avoid investigator bias during tissue preparation and data analysis.…”

“…Genomic DNA was extracted from 43 fresh-frozen tissue samples that matched the TMA samples in cohort A with the DNeasy Blood & Tissue Kit (Qiagen) according to the manufacturer’s protocol. 17 The DNA integrity number was 4.0, which was calculated using an Agilent 2000 TapeStation (Agilent Technologies, Waldbronn, Germany). A genomic DNA library was constructed using GeneRead DNAseq Targeted Panel V.2 (Human Comprehensive Cancer Panel) and covered more than 95% of the total exon regions of 160 cancer-related genes.…”

From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma

“…A histological analysis of LAG-3, TIM-3, and TIGIT identified distinct intra-tumoral phenotypes dominated primarily by a single checkpoint. In this study, the LAG-3 cluster was associated with a CD39+ exhausted CD8 T cell-and macrophage-dominant phenotype, and the TIGIT cluster with higher CTLA-4 expression [112]. Finally, multiple immune checkpoints, including PD-L1, PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT, have been associated with genomic instability [113], long noncoding RNAs [114], TNFRSF9 expression and TNFRSF9+ CD8 TILs [115], and CXCL13+ CD8 TILs [116] in RCC.…”