2. Academic Validation
  3. mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma

mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma

  • J Pathol. 2026 Jan;268(1):77-88. doi: 10.1002/path.6490.
Huili Li 1,  Adrianna Amaral 1,  Thiago Vidotto 1,  Juhyung Woo 1,  Hans B Liu 1,  Lia D Oliveira 1,  Oluwademilade Dairo 1,  Kewen Feng 2,  Eugene Shenderov 2,  Pedram Argani 1,  Laura S Schmidt 3 4,  W Marston Linehan 3,  Tamara L Lotan # 1 2 5,  Kaushal Asrani # 1 5
Affiliations

Affiliations

  • 1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 4 Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 5 Department of Urology and Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • # Contributed equally.
PMID: 41178060 DOI: 10.1002/path.6490
Abstract

Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate Cancer and may be expanded to additional tumor types with high expression, such as those with mTOR signaling activation. MiT/TFE-rearranged translocation renal cell carcinoma (tRCC) is a rare, aggressive subtype that is relatively immune-depleted, with high levels of mTOR activity. Thus, we assessed B7-H3 expression in preclinical tRCC models and human tRCC samples. As hypothesized, we found that induction of TFE3 fusion proteins, including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3, is associated with upregulation of B7-H3 in multiple human preclinical tRCC cell line systems and transgenic mouse models. Pharmacologic or genetic inhibition of mTOR signaling is sufficient to downregulate B7-H3 expression in inducible and patient-derived, human cell line models of tRCC. In keeping with these preclinical results, human tRCC demonstrated significantly higher gene expression of CD276 than normal kidney, across five of the six fusions studied. At the protein level, tRCC had higher tumor cell B7-H3 intensity and proportion scores than normal kidney or clear cell RCC (ccRCC). B7-H3 expression in tumor vasculature was similar in tRCC and ccRCC, both of which showed significantly higher expression than normal kidney. Within tRCC cases, higher CD276 expression was observed in metastatic compared to localized tumors and was associated with lower tumoral CD4+ T-cell content by bulk RNAseq deconvolution. Taken together, tRCC fusion proteins upregulate B7-H3 expression via increased mTOR signaling, resulting in a higher tumoral B7-H3 expression compared to normal kidney or conventional RCC, suggesting that B7-H3 may be a promising therapeutic target in tRCC. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords

B7‐H3; GPNMB; TFE3; TFEB; mTOR; renal cell carcinoma; translocation renal cell carcinoma (tRCC).

Figures
Products
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    Product Name
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    Target
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  • HY-132168
    99.94%, mTORC1 Inhibitor