CD8 and PD-L1 determination in lung tumor tissue as prognostic biomarker and predictive marker of anti PD-1 efficacy
Jean David Fumet1, Fanny Ledys1, Corentin Richard1, Romain Boidot1, Valentin Derangere1, Francois Ghiringhelli1 1CentreGeorges-François Leclerc, Dijon, France Hypothesis: With recent approval of mAb targeted PD-1 and PDL1 in non-small cell lung cancer (NSCLC), extensive efforts are under way to develop predictive biomarkers. PD-L1 expression upon histology is the only clinically available biomarker. Transcriptomic immune signature is also emerging. While the efficacy of these drugs is dependent of CD8 T cells, no study evaluates both CD8 and PD-L1 as biomarkers. Methods: We used RNA sequencing data from lung cancers from TCGA as a prognostic cohort. We next validated transcriptomic data by immunohistochemistry using another prognostic cohort of 34 metastatic NSCLC untreated by immunotherapy. Predictive studies were also conducted on samples from 78 NSCLC patients treated with nivolumab, characterized for outcome. CD8 and PD-L1 expression was studied by RNA sequencing and immunohistochemistry (IHC). As control, we used IFN and Immune Expanded Signatures (IES) previously described as gold standard. Results: In the prognostic TCGA Cohort, we observed that high CD8 mRNA is associated with better overall survival while PD-L1 is associated with poor prognosis using mRNA independently of tumor stage or histology. CD8 and PDL1 expression determined upon IHC was also prognosis in the prognostic cohort. In the predictive cohort, CD8 and PD-L1 using mRNA or IHC are associated with better progression-free or overall-survival in patients treated with nivolumab. Combination of both variables is highly predictive of outcome and remained significant on multivariable analysis. This 2 gene signature using either IHC or mRNA outperforms both IFN and IES signature. Similar results were obtained in an external cohort from Gene Expression Omnibus (GSE93157). Conclusions: CD8 and PDL1 mRNA or IHC could be used to address NSCLC outcome under nivolumab treated patients. Further studies are warranted to validate the predictive role of this combinatory variable.
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