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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

abstract

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.
   
citation Gachechiladze M, Škarda J, Skanderová D, Überall I, Kolek V, Smičkova P, Vojta P, Vbrková J, Hajdúch M, Shani I, Kolář Z, Stahel R, Weder W, Rulle U, Soltermann A, Joerger M. 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. Lung Cancer 2020; 147:30-38.
   
type journal paper/review (English)
date of publishing 23-06-2020
journal title Lung Cancer (147)
ISSN electronic 1872-8332
pages 30-38
PubMed 32653671
DOI 10.1016/j.lungcan.2020.06.025