Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinoma-A finding with therapeutic potential.
Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p = 0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p = 0.01), metastases at diagnosis (p = 0.01), a sarcomatoid component (p = 0.04), overexpression of VEGF (p = 0.006), and cytoplasmic PAR-3 expression (p = 0.01). PD-L1 expression was also associated with dense PD-1 expression (p = 0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors; p = 0.007) that remained significant after multivariate analysis (p = 0.004 and p = 0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.
Department of Pathology, University Hospital, Rennes, France.|UMR 6290-IGDR, Rennes, France.
Solène-Florence
SF
Kammerer-Jacquet
Department of Oncology, Eugène Marquis Center, Rennes, France.
Laurence
L
Crouzet
Department of Oncology, Eugène Marquis Center, Rennes, France.
Angélique
A
Brunot
Department of Pathology, University Hospital, Rennes, France.|UMR 6290-IGDR, Rennes, France.
Julien
J
Dagher
EHESP, Rennes, France.
Adélaïde
A
Pladys
Department of Oncology, Eugène Marquis Center, Rennes, France.
Julien
J
Edeline
Department of Oncology, Eugène Marquis Center, Rennes, France.
Brigitte
B
Laguerre
Department of Urology, University Hospital, Rennes, France.
Benoit
B
Peyronnet
Department of Urology, University Hospital, Rennes, France.
Romain
R
Mathieu
Department of Urology, University Hospital, Rennes, France.
Grégory
G
Verhoest
Department of Urology, University Hospital, Kremlin Bicêtre, France.
Jean-Jacques
JJ
Patard
Department of Molecular Biology, University Hospital, Rennes, France.
Alexandra
A
Lespagnol
Department of Molecular Biology, University Hospital, Rennes, France.
Jean
J
Mosser
Department of Molecular Biology, University Hospital, Nantes, France.
Marc
M
Denis
Laboratory Integrative Tumor Immunology and Genetic Oncology, INSERM UMR1186, Villejuif, France.
Yosra
Y
Messai
Laboratory Integrative Tumor Immunology and Genetic Oncology, INSERM UMR1186, Villejuif, France.
Sophie
S
Gad-Lapiteau
Laboratory Integrative Tumor Immunology and Genetic Oncology, INSERM UMR1186, Villejuif, France.
Salem
S
Chouaib
UMR 6290-IGDR, Rennes, France.|Department of Cytogenetics, University Hospital, Rennes, France.
Marc-Antoine
MA
Belaud-Rotureau
Department of Urology, University Hospital, Rennes, France.
Karim
K
Bensalah
Department of Pathology, University Hospital, Rennes, France.|UMR 6290-IGDR, Rennes, France.
Nathalie
N
Rioux-Leclercq
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
PD-L1 expression; VHL status; clear cell renal cell carcinoma; clinical outcome