Abstract
PurposeEnhancer of zeste homolog 2 (EZH2), the catalytic part of the Polycomb repressive complex 2 (PRC2), has a prognostic role in renal cell carcinoma (RCC) and was recently shown to modulate the immune response by reducing tumor cell immunogenicity.MethodsTo investigate whether the prognostic role of EZH2 might be driven by a modified immune environment, more than 1800 RCCs were analyzed in a tissue microarray for EZH2 expression and CD8 positive lymphocytes were quantitated by automated digital imaging.ResultsEZH2 positivity was found in 75.2% of 1603 interpretable tumors. In clear cell RCC, high EZH2 expression was significantly linked to high ISUP, Furmann, and Thoenes grade (p < 0.0001 each), advanced stage (p < 0.0001), nodal (p = 0.0190) and distant metastasis (p < 0.0001) as well as shortened overall (p < 0.0027) and recurrence free survival (p < 0.0001). The density of CD8+ cells varied from 0 to 5048 cells/mm2 (Median 120 cells/mm2). A high CD8+ count was significantly associated with high ISUP, Fuhrmann, and Thoenes grade (p < 0.0001 each), advanced tumor stage (p = 0.0041), distant metastasis (p = 0.0026) as well as reduced overall survival (p = 0.0373) and recurrence free survival (p = 0.0450). The density of CD8+ cells continuously increased with raising EZH2 levels (p < 0.0001).ConclusionOur data support a striking prognostic role of both EZH2 expression and the density of CD8+ cells in RCC. The tight relationship of EZH2 expression and CD8+ cell counts in RCC is consistent with models suggesting that EZH2 overexpression can be caused by high lymphocyte content in certain tumor types. Such a mechanism could explain the unique finding of high lymphocyte counts driving poor prognosis in RCC patients.
Highlights
Renal cell carcinoma (RCC) is one of the most common tumors worldwide [1]
Enhancer of zeste homolog 2 (EZH2) positivity was found in 75.2% of 1603 analyzable cancers, including 63.1% tumors with weak, 8.0% with moderate, and 4.1% with strong immunostaining according to our criteria
In clear cell RCC, high EZH2 expression was significantly linked to high ISUP, Fuhrmann, and Thoenes grade (p < 0.0001 each), advanced stage (p < 0.0001), nodal metastasis (p = 0.0190), and distant metastasis (p < 0.0001)
Summary
Renal cell carcinoma (RCC) is one of the most common tumors worldwide [1]. Localized tumors are generally treated surgically, whereas for advanced tumors necessitating systemic treatment, several new drugs were approved lately and have improved the still unfavorable prognosis of Current clinical trials evaluate whether adjuvant application of immune-checkpoint inhibitors or other new drugs can improve the prognosis of patients with kidney cancer in high risk situations, such as tumor recurrence or progression after nephrectomy (Keynote-564, IMmotion, Checkmate-914). Through trimethylation of Histone 3 on lysine 27 (H3K27me3) it induces chromatin compaction and transcriptional repression of various genes including p16 and E-Cadherin [11, 12]. Studies have suggested that high levels of EZH2 expression in cancer tissue may be strongly linked to poor patient prognosis. This includes several studies on kidney cancer [14,15,16,17,18,19,20,21,22]. EZH2 has recently been shown to modulate the immune response to tumor cells by reducing their immunogenicity [23]
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