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Klümper, Niklas; Ralser, Damian J; Zarbl, Romina; Schlack, Katrin; Schrader, Andres Jan; Rehlinghaus, Marc; Hoffmann, Michèle J; Niegisch, Günter; Uhlig, Annemarie; Trojan, Lutz; Steinestel, Julie; Steinestel, Konrad; Wirtz, Ralph M; Sikic, Danijel; Eckstein, Markus; Kristiansen, Glen; Toma, Marieta; Hölzel, Michael; Ritter, Manuel; Strieth, Sebastian; Ellinger, Jörg; Dietrich, Dimo

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

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  • Medientyp: E-Artikel
  • Titel: 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
  • Beteiligte: Klümper, Niklas; Ralser, Damian J; Zarbl, Romina; Schlack, Katrin; Schrader, Andres Jan; Rehlinghaus, Marc; Hoffmann, Michèle J; Niegisch, Günter; Uhlig, Annemarie; Trojan, Lutz; Steinestel, Julie; Steinestel, Konrad; Wirtz, Ralph M; Sikic, Danijel; Eckstein, Markus; Kristiansen, Glen; Toma, Marieta; Hölzel, Michael; Ritter, Manuel; Strieth, Sebastian; Ellinger, Jörg; Dietrich, Dimo
  • Erschienen: BMJ, 2021
  • Erschienen in: Journal for ImmunoTherapy of Cancer, 9 (2021) 8, Seite e002949
  • Sprache: Englisch
  • DOI: 10.1136/jitc-2021-002949
  • ISSN: 2051-1426
  • Schlagwörter: Cancer Research ; Pharmacology ; Oncology ; Molecular Medicine ; Immunology ; Immunology and Allergy
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  • Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>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 <jats:italic>CTLA4</jats:italic> promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate <jats:italic>CTLA4</jats:italic> methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p><jats:italic>CTLA4</jats:italic> 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, <jats:italic>CTLA4</jats:italic> methylation as well as CD8<jats:sup>+</jats:sup> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>CTLA4</jats:italic> promoter hypomethylation was significantly correlated with <jats:italic>CTLA4</jats:italic> 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, <jats:italic>CTLA4</jats:italic> promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of <jats:italic>CTLA4</jats:italic> hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, <jats:italic>CTLA4</jats:italic> 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).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our study suggests <jats:italic>CTLA4</jats:italic> methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.</jats:p></jats:sec>
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