Immune checkpoint B7‐H3 protein expression is associated with poor outcome and androgen receptor status in prostate cancer

Nunes‐Xavier, Caroline E.; Kildal, Wanja; Kleppe, Andreas; Danielsen, Håvard E.; Wæhre, Håkon; Llarena, Roberto; Mælandsmo, Gunhild M.; Fodstad, Øystein; Pulido, Rafael; López, José I.

doi:10.1002/pros.24180

Cited by 17 publications

(9 citation statements)

References 48 publications

(98 reference statements)

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“…Previous studies have reported higher levels of AR protein expression in patients with higher B7‐H3 protein expression 5,27 and an enrichment of AR signaling‐related gene expression signatures among those with higher B7‐H3 mRNA expression 2 . Next, we investigated whether the AR‐A score, a previously reported 9‐gene signature of AR‐A in the intermediate‐risk/high‐risk subcohort, 17 was correlated with B7‐H3 protein or mRNA expression (Table 3).…”

Section: Resultsmentioning

confidence: 91%

Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Mendes

Kaur

et al. 2022

Cancer

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Background B7 homolog 3 (B7‐H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD‐L1. Immunotherapies (antibodies, antibody‐drug conjugates, and chimeric antigen receptor T cells) targeting B7‐H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7‐H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7‐H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods An automated, clinical‐grade immunohistochemistry assay was developed by to digitally quantify B7‐H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results B7‐H3 protein expression was significantly lower in self‐identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7‐H3 protein expression with ERG/ETS and PTEN status. B7‐H3 messenger RNA expression, but not B7‐H3 protein expression, was significantly correlated with regulatory (FOXP3‐positive) T‐cell density. Finally, androgen receptor activity scores were significantly correlated with B7‐H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7‐H3 protein expression. Conclusions The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7‐H3 expression. Lay Summary B7‐H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7‐H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7‐H3 messenger RNA expression is correlated with the density of tumor T‐regulatory cells. Finally, in the first paired analysis of B7‐H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7‐H3 protein levels, suggesting that androgen signaling may positively regulate B7‐H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.

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Section: Resultsmentioning

confidence: 91%

Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Mendes

Kaur

et al. 2022

Cancer

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“…The PCa cohort has been previously described ( 41 ). Briefly, it consisted of 120 PCa patients treated with radical prostatectomy at Cruces University Hospital (Barakaldo, Spain) between 2000 and 2005.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer

et al. 2022

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BackgroundPyruvate dehydrogenase (PDH) complex converts pyruvate into acetyl-CoA by pyruvate decarboxylation, which drives energy metabolism during cell growth, including prostate cancer (PCa) cell growth. The major catalytic subunit of PDH, PDHA1, is regulated by phosphorylation/dephosphorylation by pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs). There are four kinases, PDK1, PDK2, PDK3 and PDK4, which can phosphorylate and inactivate PDH; and two phosphatases, PDP1 and PDP2, that dephosphorylate and activate PDH.MethodsWe have analyzed by immunohistochemistry the expression and clinicopathological correlations of PDHA1, PDP1, PDP2, PDK1, PDK2, PDK3, and PDK4, as well as of androgen receptor (AR), in a retrospective PCa cohort of patients. A total of 120 PCa samples of representative tumor areas from all patients were included in tissue microarray (TMA) blocks for analysis. In addition, we studied the subcellular localization of PDK2 and PDK3, and the effects of the PDK inhibitor dichloroacetate (DCA) in the growth, proliferation, and mitochondrial respiration of PCa cells.ResultsWe found heterogeneous expression of the PDH complex components in PCa tumors. PDHA1, PDP1, PDK1, PDK2, and PDK4 expression correlated positively with AR expression. A significant correlation of PDK2 immunostaining with biochemical recurrence and disease-free survival was revealed. In PCa tissue specimens, PDK2 displayed cytoplasmic and nuclear immunostaining, whereas PDK1, PDK3 and PDK4 showed mostly cytoplasmic staining. In cells, ectopically expressed PDK2 and PDK3 were mainly localized in mitochondria compartments. An increase in maximal mitochondrial respiration was observed in PCa cells upon PDK inhibition by DCA, in parallel with less proliferative capacity.ConclusionOur findings support the notion that expression of specific PDH complex components is related with AR signaling in PCa tumors. Furthermore, PDK2 expression associated with poor PCa prognosis. This highlights a potential for PDH complex components as targets for intervention in PCa.

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“…In cancers, B7-H3 acts as an inhibitory immune checkpoint that negatively regulates anti-tumor immunity. Overexpression of B7-H3 in tumor tissues is a poor prognostic biomarker in prostate cancer [ 29 ], upper tract urothelial carcinoma [ 30 ], small cell lung cancer [ 31 ], etc. Besides, inhibition of B7-H3 expression is a promising therapeutic strategy for human cancer.…”

Section: Discussionmentioning

confidence: 99%

Co-deficiency of B7-H3 and B7-H4 identifies high CD8 + T cell infiltration and better prognosis in pancreatic cancer

Wang

Cao

et al. 2022

BMC Cancer

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Background Immunotherapy is a novel hotspot for the treatment of pancreatic adenocarcinoma (PAAD). However, potential biomarkers which could identify the inflamed tumor microenvironment (TME) are urgently required. Methods In the present study, we measured the levels of B7-H3, B7-H4, and major tumor-infiltrating immune cells (TIICs) using bioinformatics analyses and immunohistochemistry (IHC) staining on PAAD samples represented in the tissue microarray (TMA) format. Statistical analysis and figures exhibition were performed using R 4.1.0, SPSS 26.0, and GraphPad Prism 6.0. Results B7-H3 and B7-H4 were up-regulated in PAAD compared with para-tumor tissues, and their expression exhibited no tight correlation in PAAD tissues. B7-H3 and B7-H4 were lowly expressed in well-differentiated PAAD tissues and correlated with poorly differentiated grades. Besides, single B7-H3 or B7-H4 expression exhibited limited prognostic value, but co-deficiency of B7-H3 and B7-H4 predicted a better prognosis in PAAD. Moreover, co-deficiency of B7-H3 and B7-H4 indicated immuno-hot tumors with high CD8 + T cell infiltration. Conclusions Overall, combined B7-H3 and B7-H4 expression is a promising stratification strategy to assess prognosis and immunogenicity in PAAD, which could be used as a novel classifier in clinical practice.

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Immune checkpoint B7‐H3 protein expression is associated with poor outcome and androgen receptor status in prostate cancer

Cited by 17 publications

References 48 publications

Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer

Co-deficiency of B7-H3 and B7-H4 identifies high CD8 + T cell infiltration and better prognosis in pancreatic cancer

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