Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer

Abstract

New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1), because PD-L1 expression on tumor cells has limited power for selecting patients who may benefit from such therapy. Here we investigated the significance of PD-L1 and PD-L2 gene copy number gains using fluorescence in situ hybridization as well as PD-L1 and PD-L2 expression in 654 patients with resected non-small-cell lung cancer. The prevalence of PD-L1 amplification and polysomy was 3.1% and 13.2%, respectively. The PD-L1 gene copy number status was in agreement with both the PD-L2 and Janus kinase 2 gene copy number statuses. PD-L1 and PD-L2 expression was observed in 30.7% and 13.1%, respectively. Both PD-L1 copy number gains and expression were associated with smoking-related tumors. Tumor cells with PD-L1 genomic gains exhibited significantly higher levels of PD-L1 expression than those without, but PD-L2 copy number gains were not related to PD-L2 augmentation. PD-L1 gene amplification and polysomy were independently associated with PD-L1 expression, with high immune infiltrates and EGFR expression in a multivariate logistic regression model. Comparative analysis between primary tumors and synchronous regional lymph node metastases revealed that the PD-L1 gene copy number alterations were highly consistent and reproducible compared with the PD-L1 expression. Both PD-L1 amplification and level of protein expression were predictors of poor survival using Cox univariate analyses. Therefore, we conclude that an increase in PD-L1 gene copy number can be a feasible alternative biomarker for predicting response to anti-PD-1/PD-L1 therapy.

Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells

“…Although the microarray data suggests slightly higher expression of PD-L2, another ligand for PD-1, in HCC4006ER cells, the expression level of PD-L2 is lower in lung cancers [43] and the role of PD-L2 as a predictive biomarker for anti-PD-1/PD-L1 therapy is currently unclear. We have shown that HCC4006ER cells were insensitive to anti-microtubule agents that are often used as cytotoxic agents in non-small cell lung cancers [28].…”

“…Regulation of PD-L1 expression in tumor cells is complex and affected by several mechanisms including: PD-L1 genomic gains [14], structural variations of the 3’ region of the PD-L1 gene [15], oncogenic signaling activation such as AKT serine/threonine kinase (AKT) – mechanistic target of rapamycin (mTOR) pathway [16], Janus kinase (JAK) – signal transducer and activator of transcription (STAT) pathway [17], and mitogen-activated protein kinase 1 (MAPK1) – Jun proto-oncogene, AP-1 transcription factor subunit (JUN) pathway [18]. In addition, PD-L1 expression in tumor cells is influenced by a variety of factors such as release of IFN-gamma from T cells in the tumor microenvironment in vivo [19].…”

Next generation predictive biomarkers for immune checkpoint inhibition

“…Moreover, the study demonstrated a significant difference in overall survival between PD-L1 positive and negative patients (7·2 years versus 14·0 years, respectively). [29] For this reason, PD-L1 amplification assays may be useful predictive biomarkers that may one day replace, or be performed in addition to, PD-L1 IHC.…”

Tumor immunotherapy: drug-induced neoantigens (xenogenization) and immune checkpoint inhibitors

“…Elevated expression of PD-L1 has been found to represent an adverse prognostic biomarker in NSCLC [126]. PD-L1 can be up-regulated by IFN-γ produced by tumor-infiltrating T cells thus promoting the progression of cancer [127].…”