F.O. Mildner , M.M. Sykora , H. Hackl , A. Amann , B. Zelger , S. Sprung , M.L. Buch , F. Nocera , P. Moser , H. Maier , F. Augustin , C. Manzl , F. Kocher , A. Pircher , J. Lindenmann , I Mykoliuk , S. Raftopoulou , J. Kargl , D. Wolf , S. Sopper , G. Gamerith
{"title":"可溶性PD-L1与早期非小细胞肺癌（NSCLC）的复发和总生存率无关","authors":"F.O. Mildner , M.M. Sykora , H. Hackl , A. Amann , B. Zelger , S. Sprung , M.L. Buch , F. Nocera , P. Moser , H. Maier , F. Augustin , C. Manzl , F. Kocher , A. Pircher , J. Lindenmann , I Mykoliuk , S. Raftopoulou , J. Kargl , D. Wolf , S. Sopper , G. Gamerith","doi":"10.1016/j.lungcan.2024.107955","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.</p></div><div><h3>Methods</h3><p><em>In vitro</em> T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (<em>i.e.</em> ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.</p></div><div><h3>Results</h3><p><em>In vitro</em> sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these <em>in vitro</em> and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.</p></div><div><h3>Discussion</h3><p>Although <em>in vitro</em> and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107955"},"PeriodicalIF":4.5000,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0169500224004896/pdfft?md5=6fb15516e5a0f75c49b45de97233b970&pid=1-s2.0-S0169500224004896-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)\",\"authors\":\"F.O. Mildner , M.M. Sykora , H. Hackl , A. Amann , B. Zelger , S. Sprung , M.L. Buch , F. Nocera , P. Moser , H. Maier , F. Augustin , C. Manzl , F. Kocher , A. Pircher , J. Lindenmann , I Mykoliuk , S. Raftopoulou , J. Kargl , D. Wolf , S. Sopper , G. Gamerith\",\"doi\":\"10.1016/j.lungcan.2024.107955\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.</p></div><div><h3>Methods</h3><p><em>In vitro</em> T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (<em>i.e.</em> ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.</p></div><div><h3>Results</h3><p><em>In vitro</em> sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these <em>in vitro</em> and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.</p></div><div><h3>Discussion</h3><p>Although <em>in vitro</em> and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. 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Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)
Background
Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.
Methods
In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.
Results
In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.
Discussion
Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.
期刊介绍：
Lung Cancer is an international publication covering the clinical, translational and basic science of malignancies of the lung and chest region.Original research articles, early reports, review articles, editorials and correspondence covering the prevention, epidemiology and etiology, basic biology, pathology, clinical assessment, surgery, chemotherapy, radiotherapy, combined treatment modalities, other treatment modalities and outcomes of lung cancer are welcome.
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