論文No2530
Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma
Mariam Gachechiladze, Josef Škarda, Daniela Skanderová, Ivo Überall, Vítězslav Kolek, Petra Smičkova, Petr Vojta, Jana Vbrková, Marián Hajdúch, Ilay Shani, Zdeněk Kolář, Rolf Stahel, Walter Weder, Undine Rulle, Alex Soltermann, Markus Joerger
LUNG CANCER, VOLUME 147, P30-38, SEPTEMBER 01, 2020
＜目的＞
DNA修復蛋白が、PD-L1、TIL、TMBのほかに免疫治療反応の予測因子としてでてきた。
我々は切除非小細胞肺がん(NSCLC)患者においてPD-L1、TIL、予後予測因子である相同組み換え蛋白RAD51を解析した。
＜方法＞
発見コホートはOlomouc大学（チェコ）の96名のNSCLC患者、複製コホートはZurich大学（スイス）の1109名のNSCLC患者を含んだ。
組織マイクロアレイ(TMAs)をVentana Benchmark Ultraの自動化染色プラットフォームを使用して、
RAD51, CD3, CD8, CD68, PD-L1に対する抗体で染色した。
＜結果＞
核RAD51蛋白の喪失は、ネオアジュバントの化学放射線療法(CT/RT)を受けている患者で
高TIL(r=-0.25, p = 0.01) 、PD-L1状態(10.6 vs. 2.4 %, p = 0.012)と関連していた。
TCGAデータセットのsilico解析においてRAD51 mRNA発現とCD45 (r = ‒0.422, p < 0.0001)、
CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001)
との間に負の相関を認めた。
RAD51 low/PD-L1 highの患者は複製セット、TCGAデータセットで独立したクラスターと分類された。
TILが高い状態は複製セットでOSが延長していた(unadjusted HR = 0.57, 95 % CI 0.42−0.76, p < 0.001)。
同様の結果がCD3, CD8, CD68でもみられた。
＜感想＞
DNA修復蛋白であるRAD51は化学放射線療法後の切除NSCLC手術時点でTIL増加、PD-L1高と若干関連していたようです。
TILが増加し、RAD51が核内喪失していると、切除NSCLCの予後が良好だったようです。
Objectives
DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD-L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC).
Materials and methods
Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1.
Results
Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r = ‒0.422, p < 0.0001), CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42−0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68.
Conclusions
In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemo- or radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.