Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 31;13(1):2419686.
doi: 10.1080/2162402X.2024.2419686. Epub 2024 Nov 1.

Impact of B7-H3 expression on metastasis, immune exhaustion and JAK/STAT and PI3K/AKT pathways in clear cell renal cell carcinoma

Maite Emaldi  1   2 , Esther Rey-Iborra  1   2 , Ángela Marín  1 , Lorena Mosteiro  1   2   3 , David Lecumberri  1   4 , Tove Øyjord  5 , Noémie Roncier  5 , Gunhild M Mælandsmo  5   6 , Javier C Angulo  7   8 , Peio Errarte  9 , Gorka Larrinaga  1   9 , Rafael Pulido  1   2   10 , José I López  1 , Caroline E Nunes-Xavier  1   2   5
Affiliations

Impact of B7-H3 expression on metastasis, immune exhaustion and JAK/STAT and PI3K/AKT pathways in clear cell renal cell carcinoma

Maite Emaldi et al. Oncoimmunology. .

Abstract

Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors (TKIs) are improving the response rates of advanced renal cancer patients. However, many treated patients do not respond, making novel immune checkpoint-based immunotherapies potentially clinically beneficial only for specific groups of patients. We detected high expression of the immune checkpoint protein B7-H3 in clear cell renal cell carcinomas (ccRCCs) and evaluated B7-H3 immunohistochemistry staining in tissue microarray samples from two distinct renal cancer cohorts. B7-H3 was highly expressed in approximately 50% of primary tumors and in 30% of metastatic lesions. B7-H3 expression in primary tumors correlated with tumor necrosis, sarcomatoid transformation, disease-free survival, and synchronous metastasis, while B7-H3 expression in metastasis correlated with metastases to the lymph nodes. Gene expression analysis revealed the association of B7-H3 expression with gene expression scores involved in T cell exhaustion and myeloid immune evasion, as well as with PI3K/AKT and JAK/STAT pathways. Furthermore, knocking down B7-H3 expression in renal cancer cells by siRNA and CRISPR/Cas resulted in lower 2D and 3D cell proliferation and viability as well as increased sensitivity to TKI axitinib. Together, our findings suggest a pro-oncogenic and immune evasive role for B7-H3 in ccRCC and highlight B7-H3 as an actionable novel immune checkpoint protein in combination with TKI in advanced renal cancer.

Keywords: Clear cell renal cell carcinoma (ccRCC); immune checkpoint protein B7-H3 (CD276); renal cancer.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Expression of B7 family genes in normal kidney and kidney cancer.
Figure 2.
Figure 2.
B7-H3 protein expression and Kaplan–Meier survival curves of ccRCC patients.
Figure 3.
Figure 3.
B7-H3 protein expression and Kaplan–Meier survival curves of metastatic ccRCC patients.
Figure 4.
Figure 4.
Gene expression of B7-H3 in a panel of ccRCC samples.
Figure 5.
Figure 5.
Molecular immune exhaustion panel analysis of ccRCC patients according to B7-H3 expression.
Figure 6.
Figure 6.
Molecular pan cancer pathway panel analysis of ccRCC tumor samples according to B7-H3 expression.
Figure 7.
Figure 7.
Expression of B7-H3 in renal cancer cells affects 2D and 3D viability.
See this image and copyright information in PMC

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–15. doi: 10.3322/caac.21492. - DOI - PubMed
    1. Xu W, Atkins MB, McDermott DF.. Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol. 2020;17(3):137–150. doi: 10.1038/s41585-020-0282-3. - DOI - PubMed
    1. de Velasco G, Miao D, Voss MH, Hakimi AA, Hsieh JJ, Tannir NM, de Velasco G, Tamboli P, Appleman LJ, Rathmell WK, et al. Tumor mutational load and immune parameters across metastatic renal cell carcinoma risk groups. Cancer Immunol Res. 2016;4(10):820–822. doi: 10.1158/2326-6066.CIR-16-0110. - DOI - PMC - PubMed
    1. Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909–918. doi: 10.1038/s41591-020-0839-y. - DOI - PMC - PubMed
    1. Angulo JC, Shapiro O. The changing therapeutic landscape of metastatic renal cancer. Cancers (Basel). 2019;11(9):1227. doi: 10.3390/cancers11091227. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources