• What is CD274?
  • CD274 in Lung Cancer
  • CD274 Expression
  • Clinical Trials

PD-L1 (CD274)

CD274 molecule (CD274; also known as PDL1) is a gene that encodes a protein that is known as programmed cell death 1 ligand 1 (PD-L1). The protein functions in the transmission of the costimulatory signal that is needed for T-cell proliferation. Interaction with the protein inhibits T-cell activation and proliferation. Fusions, missense mutations, nonsense mutations, silent mutations, and frameshift deletions are observed in cancers such as intestinal cancer, skin cancer, and stomach cancer.

Last Updated: January 19, 2017

PD-L1 (CD274) in Lung Cancer

As many as ~50% of lung cancers express membranous programmed cell death 1 ligand 1 (PD-L1) when less stringent cut-offs (>1%) for PD-L1 positivity are used (Huynh et al. 2016). Targeting the PD-1/PD-L1 signaling axis that leads to T cell exhaustion and subsequent immune escape by cancer cells is an emerging cancer therapeutic strategy. Antagonist antibodies to either PD-1 or PD-L1 have shown efficacy in lung cancer (see reviews in Bustamante Alvarez et al. 2015; Decatris and O’Byrne 2016; Giri et al. 2016; Leventakos and Mansfield 2016; Ohaegbulam et al. 2015; Sunshine and Taube 2015; Sznol and Chen 2013; Xia and Herbst 2016), and two antibodies to PD-1, nivolumab and pembrolizumab, have received FDA approval (Kazandjian et al. 2016; Sul et al. 2016).

Contributors: Leora Horn, M.D., M.Sc.

Suggested Citation: Horn, L. 2017. PD-L1 (CD274) in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/cd274/ (Updated January 19).

Last Updated: January 19, 2017

PD-L1 (CD274) Expression in Lung Cancer

Implications for Targeted Therapeutics
Response to PD-1 antibodies Confers increased sensitivitya
Response to PD-L1 antibodies Confers increased sensitivityb

Targeting the PD-1/PD-L1 signaling axis, which when activated leads to T cell exhaustion and subsequent immune escape by cancer cells, has proven to be an effective therapeutic strategy in lung cancer. Several antibodies targeting either PD-1 or PD-L1 have now been FDA-approved in lung cancer and other types of cancer. PD-L1 expression on tumor cells or antigen-presenting cells has been postulated as a biomarker for response to PD-1/PD-L1 inhibitors. However, determining PD-L1 positivity is not standardized; thresholds for PD-L1 positive lung cancer differ based on the antibody and assay used, whether tumor tissue or tumor-infiltrating lymphocytes are assessed, and the clinical trial (Cagle and Bernicker 2015; Cree et al. 2016; Feld and Horn 2016; Festino et al. 2016; Ilie et al. 2016; Jørgensen 2016; Lisberg and Garon et al. 2016).

a Two antibodies to PD-1, nivolumab and pembrolizumab, have received FDA approval in second-line and greater metastatic settings (Kazandjian et al. 2016; Sul et al. 2016), with the approval for pembrolizumab extended to include the first-line setting (FDA 2016a). In the clinical trials for nivolumab, PD-L1 expression status was not prognostic or predictive of therapeutic efficacy in squamous lung cancer but was predictive of response in nonsquamous non-small cell lung cancer (Feld and Horn 2016). In the clinical trials for pembrolizumab, PD-L1 expression was predictive of therapeutic efficacy, and the FDA approval includes PD-L1 positivity in the indication for use statement; this requirement is not found in the FDA approval for nivolumab (Kazandjian et al. 2016; Sul et al. 2016). The FDA has approved a companion diagnostic for PD-L1 expression for pembrolizumab and a complementary diagnostic for PD-L1 expression for nivolumab (Jørgensen 2016). However, consensus about the role for PD-L1 testing in lung cancer remains elusive. This is due in part to the lack of a uniform PD-L1 assay, with each assay used in clinical trials having its own antibody and standards for positivity. Further, given the fact that 10% of PD-L1 negative patients respond to anti-PD-1 therapy, others argue that negative results should not preclude a patient from receiving treatment and that more specific and sensitive predictive and prognostic biomarker tests are needed. For discussion of these points and others regarding PD-L1 positivity as a biomarker for prediction of response to anti-PD-1/anti-PD-L1 blockade, see comments in Asmar and Rizvi 2015; Cagle and Bernicker 2015; Cree et al. 2016; Dang et al. 2016; Decatris and O’Byrne 2016; Feld and Horn 2016; Festino et al. 2016; Ilie et al. 2016; Johnson et al. 2014; Jørgensen 2016; Khoja et al. 2015; Leventakos and Mansfield 2016; Lisberg and Garon et al. 2016; Meng et al. 2015; Sunshine and Taube 2015; Sznol and Chen 2013; Xia and Herbst 2016.

b The PD-L1 antibody atezolizumab received accelerated FDA approval as second-line therapy following platinum-containing chemotherapy in NSCLC, regardless of PD-L1 expression status (FDA 2016b). Atezolizumab was more efficacious in current/former smokers than never smokers and in NSCLC tumors with tumor infiltrating immune cell PD-L1 expression on ≥10% of cells per area (Herbst et al. 2014). Tumor cell expression of PD-L1 was not associated with response in any tumor types (Herbst et al. 2014). Subsequent studies have found correlation with PD-L1 expression on either immune or tumor cells and response to atezolizumab (Fehrenbacher et al. 2016; Spigel et al. 2015; Spira et al. 2015). Other PD-L1 antibodies, including durvalumab and avelumab, have also shown promising results in NSCLC, with better response associated with PD-L1 positivity (Antonia et al. 2016; Brahmer et al. 2014; Gulley et al. 2015a; Gulley et al. 2015b; Rizvi et al. 2015). However, because some patients respond to anti-PD-L1 therapy in the absence of PD-L1 positivity, there is ongoing discussion about the use of PD-L1 testing in the clinical setting. For discussion of these points and others regarding PD-L1 positivity as a biomarker for prediction of response to anti-PD-1/anti-PD-L1 blockade, see comments in Asmar and Rizvi 2015; Cagle and Bernicker 2015; Cree et al. 2016; Dang et al. 2016; Decatris and O’Byrne 2016; Feld and Horn 2016; Festino et al. 2016; Ilie et al. 2016; Johnson et al. 2014; Jørgensen 2016; Khoja et al. 2015; Leventakos and Mansfield 2016; Lisberg and Garon et al. 2016; Meng et al. 2015; Sunshine and Taube 2015; Sznol and Chen 2013; Xia and Herbst 2016.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc.

Suggested Citation: Lovly, C., L. Horn. 2017. PD-L1 (CD274) Expression in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/cd274/359/ (Updated January 19).

Last Updated: January 19, 2017

My Cancer Genome has released its new and improved cancer clinical trials search tool on our beta website. Please visit beta.padiracinnovation.org to check it out!

Disclaimer: The information presented at padiracinnovation.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.