Universität zu Köln

Kluemper, Niklas, Ralser, Damian J., Zarbl, Romina, Schlack, Katrin, Schrader, Andres Jan, Rehlinghaus, Marc, Hoffmann, Michele J., Niegisch, Guenter, Uhlig, Annemarie, Trojan, Lutz, Steinestel, Julie, Steinestel, Konrad, Wirtz, Ralph M., Sikic, Danijel, Eckstein, Markus, Kristiansen, Glen, Toma, Marieta, Hoelzel, Michael, Ritter, Manuel, Strieth, Sebastian, Ellinger, Joerg and Dietrich, Dimo (2021). 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. J. Immunother. Cancer, 9 (8). LONDON: BMJ PUBLISHING GROUP. ISSN 2051-1426

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Abstract

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<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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kluemper, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Ralser, Damian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zarbl, Romina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlack, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Andres Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehlinghaus, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Michele J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niegisch, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED Uhlig, Annemarie UNSPECIFIED UNSPECIFIED UNSPECIFIED Trojan, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinestel, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinestel, Konrad UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirtz, Ralph M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sikic, Danijel UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckstein, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Kristiansen, Glen UNSPECIFIED UNSPECIFIED UNSPECIFIED Toma, Marieta UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelzel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritter, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Strieth, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellinger, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietrich, Dimo UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-600030
DOI:	10.1136/jitc-2021-002949
Journal or Publication Title:	J. Immunother. Cancer
Volume:	9
Number:	8
Date:	2021
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2051-1426
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-METHYLATION; CANCER; SURVIVAL; PITX2 Multiple languages Oncology; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60003