CTLA4 promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma
Creators: name: Klümper, Niklas
name: Ralser, Damian J.
name: Zarbl, Romina
name: Schlack, Katrin
name: Schrader, Andres Jan
name: Rehlinghaus, Marc
name: Hoffmann, Michele J.
name: Niegisch, Günter
name: Uhlig, Annemarie
name: Trojan, Lutz
name: Steinestel, Julie
name: Steinestel, Konrad
name: Wirtz, Ralph M.
name: Sikic, Danijel
name: Eckstein, Markus
name: Kristiansen, Glen
name: Toma, Marieta
name: Hölzel, Michael
name: Ritter, Manuel
name: Strieth, Sebastian
name: Ellinger, Jörg
name: Dietrich, Dimo
Publisher: name: Universität Ulm
Year: 2021
Subjects: subject: PITX2
subject: Cancer
subject: Survival
subject: DDC 610 / Medicine &amp; health
subject: Biomarkers
subject: Immunotherapy
subject: Urologic neoplasms; Drug therapy
subject: Kidney neoplasms
subject: DNA methylation
subject: Tumor
subject: Harnwegskrebs
subject: Nierenkrebs
subject: Methylierung

description: Background In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. Methods CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post–tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. Results CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p&lt;0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003). Conclusions Our study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.