Immune checkpoint blockade as a potential therapeutic strategy for undifferentiated malignancies

• Published in: Human pathology Vol. 82; pp. 39 - 45
• Main Authors: Devereaux, Kelly A., Charu, Vivek, Zhao, Shuchun, Charville, Gregory W., Bangs, Charles D., van de Rijn, Matt, Cherry, Athena M., Natkunam, Yasodha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2018; Elsevier Limited
• Subjects: 9p24.1 alterations; Cancer; Checkpoint inhibitors; Cloning; Gene expression; Immune checkpoint; Immunotherapy; Lymphatic system; Medical prognosis; Pathology; PD-L1; Protein expression; Proteins; Review boards; Studies; Tumors; Undifferentiated carcinoma; Undifferentiated malignancy; PD-L1; Checkpoint inhibitors; Undifferentiated carcinoma; Immune checkpoint; 9p24.1 alterations; Undifferentiated malignancy
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2018.06.034

Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors that pose not only a diagnostic challenge but also a challenge for clinical management. Most tumors in this category are currently treated empirically with nonspecific chemotherapeutic agents that yield extremely poor clinical response. Given that UMs are inherently genetically unstable neoplasms with the potential for immune dysregulation and increased neoantigen production, they are likely to be particularly amenable to immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases previously diagnosed as an “undifferentiated” malignancy and found that 56% (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ hybridization (FISH) was performed on 24 of these cases and demonstrates a genetic gain at both loci in 62.5% of UMs. Genetic alterations at the CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by FISH. Overall, we found that a significant proportion of UMs express PD-L1 and provide molecular support for using checkpoint inhibitors as a treatment approach for this class of tumors.
•Undifferentiated malignancies (UMs) are genetically complex tumors with a poor prognosis.•A high proportion of UMs show increased PD-L1 protein expression.•CD274(PD-L1) and PDCD1LG2(PD-L2) alterations lead to aberrant PD-L1 protein expression.•Immune checkpoint blockade is a novel and potentially effective treatment strategy for UMs.