Chin-Cheng Lee1, Kuo-Hao Ho2, Tzu-Wen Huang3, Chwen-Ming Shih2, Shao-Yuan Hsu4, Ann-Jeng Liu5, Ku-Chung Chen6. 1. Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. 2. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 3. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 4. Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan. 5. Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan. Electronic address: DAB90@tpech.gov.tw. 6. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: kuchung@tmu.edu.tw.
Abstract
AIMS: Immune checkpoints regulate immunity to prevent autoimmunity and protect the host from damage during pathogenic infection. They also participate in subverting immune surveillance and promote antitumor immunity in cancers. Although immunotherapy improves clinical outcomes, not all cancer patients experience expected responses after therapy. Hence, it would be meaningful to explore crucial immune checkpoints in cancers for future immunotherapies. METHODS AND KEY FINDINGS: By analyzing pan-cancer data in The Cancer Genome Atlas (TCGA), cluster of differentiation 276 (CD276), also known as B7H3, was found to be a risk gene in several cancers. A positive correlation existed between CD276 and natural killer (NK) cell infiltration. Overexpression of CD276 attenuated NK cell-mediated cell killing. Furthermore, CD276 levels showed a significant negative association with microRNA (miR)-29c-3p. Overexpression of miR-29c-3p rescued CD276-reduced NK cell cytotoxicity. According to gene set enrichment analyses, CD276-associated genes were found to be enriched in genes that targeted Myc. A negative correlation existed between miR-29 expression and Myc activity. CD276 enhanced Myc phosphorylation levels while suppressing miR-29c-3p expression. In contrast, miR-29c-3p inhibited CD276 expression, leading to reduced Myc activity. Myc suppressed miR-29c-3p expression while promoting CD276 upregulation. SIGNIFICANCE: These findings suggest that a negative regulatory loop among CD276, Myc, and miR-29c-3p influences cancer cells against NK cell cytotoxicity.
AIMS: Immune checkpoints regulate immunity to prevent autoimmunity and protect the host from damage during pathogenic infection. They also participate in subverting immune surveillance and promote antitumor immunity in cancers. Although immunotherapy improves clinical outcomes, not all cancer patients experience expected responses after therapy. Hence, it would be meaningful to explore crucial immune checkpoints in cancers for future immunotherapies. METHODS AND KEY FINDINGS: By analyzing pan-cancer data in The Cancer Genome Atlas (TCGA), cluster of differentiation 276 (CD276), also known as B7H3, was found to be a risk gene in several cancers. A positive correlation existed between CD276 and natural killer (NK) cell infiltration. Overexpression of CD276 attenuated NK cell-mediated cell killing. Furthermore, CD276 levels showed a significant negative association with microRNA (miR)-29c-3p. Overexpression of miR-29c-3p rescued CD276-reduced NK cell cytotoxicity. According to gene set enrichment analyses, CD276-associated genes were found to be enriched in genes that targeted Myc. A negative correlation existed between miR-29 expression and Myc activity. CD276 enhanced Myc phosphorylation levels while suppressing miR-29c-3p expression. In contrast, miR-29c-3p inhibited CD276 expression, leading to reduced Myc activity. Myc suppressed miR-29c-3p expression while promoting CD276 upregulation. SIGNIFICANCE: These findings suggest that a negative regulatory loop among CD276, Myc, and miR-29c-3p influences cancer cells against NK cell cytotoxicity.