Programmed Death Ligand-1 Immunohistochemistry— A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society

Abstract

The binding of programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2) to PD-1 blocks T-cell–mediated immune response to tumor. Antibodies that target programmed death receptor-1 (PD-1) will block the ligand-receptor interface, thereby allowing T cells to attack the tumor and increase antitumor immune response. In clinical trials, PD-1 inhibitors have been associated with an approximately 20% overall response rate in unselected patients with non–small cell lung cancer, with sustained tumor response in a subset of patients treated by these immune checkpoint inhibitors. Facing a proliferation of PD-L1 immunohistochemistry clones, staining platforms, and scoring criteria, the pathologist must decide on the feasibility of introducing a newly approved companion diagnostic assay that may require purchase not only of a specific antibody kit but of a particular staining platform. Given the likely reality that clinical practice may, in the near future, demand access to 4 different PD-L1 antibodies coupled with different immunohistochemistry platforms, laboratories will be challenged with deciding among this variety of testing methods, each with its own potential benefits. Another immediate challenge to PD-L1 testing in lung cancer patients is that of access to adequate tumor tissue, given that non–small cell lung cancer samples are often extremely limited in size. With PD-L1 testing it has become clear that the historically used US regulatory approach of one assay–one drug will not be sustainable. One evolving concept is that of complementary diagnostics, a novel regulatory pathway initiated by the US Food and Drug Administration, which is distinct from companion diagnostics in that it may present additional flexibility. Although pathologists need to face the practical reality that oncologists will be asking regularly for the PD-L1 immunohistochemistry status of their patients' tumors, we should also keep in mind that there may be room for improvement of biomarkers for immunotherapy response. The field is rich with opportunities for investigation into biomarkers of immunotherapy response, particularly in the form of collaborative, multidisciplinary studies that incorporate oncologists, pathologists, and basic scientists. Pathologists must take the lead in the rational incorporation of these biomarkers into clinical practice.

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

“…First, there is currently no gold standard in PD-L1 testing, and a number of different antibodies and scoring protocols have been applied. 23 To account for this, we used a commercially available, anti-PD-L1 antibody that has been independently validated. [24][25][26] We also evaluated PD-L1 expression using cut-offs that have been associated with beneficial response to PD-1/PD-L1 inhibitors in clinical studies.…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Therefore, PD-L1 testing should be used for patient selection only when planning to administer pembrolizumab in patients with NSCLC (except when pembrolizumab is used in first line [1 L] in combination with chemotherapy) or gastric/gastroesophageal junction adenocarcinoma [13]. Despite the development of FDA-approved assays for PD-L1 testing, some clinics use laboratorydeveloped tests, which can be less costly but can also increase the amount of testing variability [86]. Variability in PD-L1 testing can arise because of the type (tumor cells, immune cells, or a combination) and percentage cutoffs used for positivity, archival versus fresh tissue, primary versus metastatic biopsies, diversity of antibodies utilized, and tumor heterogeneity [86,87].…”

“…Despite the development of FDA-approved assays for PD-L1 testing, some clinics use laboratorydeveloped tests, which can be less costly but can also increase the amount of testing variability [86]. Variability in PD-L1 testing can arise because of the type (tumor cells, immune cells, or a combination) and percentage cutoffs used for positivity, archival versus fresh tissue, primary versus metastatic biopsies, diversity of antibodies utilized, and tumor heterogeneity [86,87]. Several comparative studies across different PD-L1 assays have been conducted, including collaborative studies between industry and academic institutions [88][89][90][91].…”

Lung Carcinoma Predictive Biomarker Testing by Immunoperoxidase Stains in Cytology and Small Biopsy Specimens: Advantages and Limitations

“…Some attempts have been made to standardize IPOX protocols, especially for biomarkers, 24,25 and the Food and Drug Administration (FDA) recently approved IPOX assays for the detection of anaplastic lymphoma kinase (ALK) rearrangement (D5F3 clone, Ventana Medical Systems, Oro Valley, Arizona) and programmed death ligand-1 (PD-L1) expression (Dako, Carpinteria, California) as companion diagnostic tests to identify patients eligible for targeted therapies. 26 However, even when a protocol is optimized, validated, and consistently applied, consistency of interpretation may be challenging to achieve.…”

“…Two PD-L1 antibody assays (Dako) were recently FDA approved as nonessential and essential companion diagnostic tests for the use of 2 targeted drugs. 25,64,65 However, their use is still limited because there is no agreement on their interpretation. Other clones are being validated for use with other targeted drugs.…”