Abstract
e20500 Background: Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and PD-L1 expression has been served as crucial predictive biomarkers for immunotherapies. However, PD-L1 expression has been found to be influenced by some extrinsic or intrinsic factors in vitro or to be associated with other biomarkers in vivo. Methods: An amount of tumor tissues was taken from a biopsy or surgery for PD-L1 expression assay and genomic profiling in Chinese lung adenocarcinoma patients using extend targeted sequencing panel. In-depth retrospective analyses of clinical features, gene alternations, singling pathways and immune signatures was conducted in negative group (TPS < 1%), intermediate group (1% ≤ TPS < 50%), and high group (TPS ≥ 50%). Clinical responses to selected mutation were also evaluated from public database such as TCGA and MSKCC. Results: A total of 248 Chinese patients with lung adenocarcinoma was retrospectively identified and included in this study, consisting of negative group (n = 124, 50%), intermediate group (n = 93, 38%), and high group (n = 38, 12%). High tumor mutation burden was significantly as associated with high PD-L1 expression. In addition, PD-L1 expression was highly related with gene alternations such as PRKDC, KMT2D, ERBB2 and SETD2. Moreover, signaling pathways of DDR, TP53, cell cycles and NOTCH also obviously related with PD-L1 expression. Besides, most of patients in high PD-L1 group were determined as high-grade immune subtypes (C2-C4), showing significant higher levels of IFN-gamma, CD8+ T-cells, NK cells, NK CD56 dim cells, Th1 cells, Th2 cells (P < 0.0001). Moreover, the prognostic value of SETD2 mutation was slight positive with overall survival from MSKCC cohort (HR 1.92 [95%CI 0.90-4.10], P = 0.085), and the percentage of IFN-gamma was significantly higher in SETD2 mutant group than in wild-type subgroup ( P < 0.01). Conclusions: This study illustrated in-depth genomic profiles and immune signatures of PD-L1 expression in Chinese lung adenocarcinoma patients, which might interpret more potential molecular mechanisms for anti-cancer immunotherapy in NSCLC. In addition, SETD2 may be potential biomarkers for predicting patients’ prognosis.
Highlights
Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and programmed death-ligand 1 (PD-L1) expression has been served as crucial predictive biomarkers for immunotherapies
Based on several clinical trials, programmed death 1 (PD-1) inhibitor-pembrolizumab has been approved by FDA as the front-line therapy for advanced lung cancer patients who present high PD-L1 expressions (TPS > 50%) and are diagnosed as EGFR or ALK negative[10] and as the front-line single-agent immunotherapy for metastatic non-small cell lung cancer (NSCLC) patients who have positive PD-L1 expression (TPS ≥ 1%) and have processed on or after platinum-based chemotherapy[11]
According to the results of PD-L1 expression essay, these patients were divided into three group, PD-L1 negative group with a tumor proportion score (TPS) < 1% (n = 124, 50%), PD-L1 intermediate group with a TPS 1%-49% (n = 93, 38%), and PD-L1high group with a TPS ≥ 50% (n = 38, 12%) (Table 1)
Summary
Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and PD-L1 expression has been served as crucial predictive biomarkers for immunotherapies. Immune checkpoint blockades (ICBs), including programmed death 1 (PD-1) blockade and cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade, have recently revolutionized the treatments for NSCLC and has emerged as a promising therapeutic strategy for NSCLC patients [6, 7]. As there were still a certain number of patients who cannot benefit from ICBs, predictive biomarkers for clinical responses to the immunotherapies such as programmed death-ligand 1 (PD-L1) expression has provided clinical assistance for clinicians in early selection of those responders and timely implementation of therapeutic regimens [6, 7]. Based on several clinical trials, PD-1 inhibitor-pembrolizumab has been approved by FDA as the front-line therapy for advanced lung cancer patients who present high PD-L1 expressions (TPS > 50%) and are diagnosed as EGFR or ALK negative[10] and as the front-line single-agent immunotherapy for metastatic NSCLC patients who have positive PD-L1 expression (TPS ≥ 1%) and have processed on or after platinum-based chemotherapy[11]
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