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  3. Comprehensive pan-cancer analysis of KLRB1-CLEC2D pair and identification of small molecule inhibitors to disrupt their interaction

Comprehensive pan-cancer analysis of KLRB1-CLEC2D pair and identification of small molecule inhibitors to disrupt their interaction

  • Int Immunopharmacol. 2024 Oct 25:140:112908. doi: 10.1016/j.intimp.2024.112908.
Yaoyao Zhu 1,  Huajie Zhang 2,  Ruoyang Shao 2,  Xintong Wu 3,  Yike Ding 3,  Yanzi Li 1,  Weiwei Wang 3,  Bingqing Li 3,  Peiyuan Lu 4,  Zhongrui Ma 5
Affiliations

Affiliations

  • 1 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China.
  • 2 Department of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China.
  • 3 Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China. Electronic address: pylu@sdfmu.edu.cn.
  • 5 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China. Electronic address: mazhongrui@sdfmu.edu.cn.
PMID: 39133960 DOI: 10.1016/j.intimp.2024.112908
Abstract

The interplay between immune checkpoints KLRB1 and CLEC2D is crucial for tumor progression and immune evasion, yet the interaction dynamics are not fully understood. This study aims to elucidate the interaction across various cancers and identify small molecule inhibitors that can disrupt it. We perform a comprehensive pan-cancer analysis of the KLRB1-CLEC2D pair, including mRNA expression patterns, pathological stages, survival outcomes, and single-cell omics, immune infiltration, copy number variations, and DNA methylation profiles. Our findings reveal a consistently higher CLEC2D/KLRB1 ratio in most Cancer types compared to normal tissues, and this ratio also increased with advancing pathological stages. Lower KLRB1 expression correlated with higher mortality in most cancers, opposite to CLEC2D. Expression variations were attributed to differential lymphocyte infiltration, CNV, and DNA methylation. Structure-based virtual screening analysis identified compounds including forsythiaside A and RGD Peptides as effective inhibitors of the KLRB1-CLEC2D interaction, validated through microscale thermophoresis. This research advances understanding of the KLRB1-CLEC2D interaction within the tumor microenvironment and introduces novel therapeutic strategies to modulate this interaction.

Keywords

CLEC2D; Forsythiaside A; KLRB1; Pan-cancer; RGD peptide; Small molecule inhibitor.

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