Short Communication Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type Zoran Gatalica 1 , Carrie Snyder 2 , Todd Maney 1 , Anatole Ghazalpour 1 , Daniel A. Holterman 1 , Nianqing Xiao 1 , Peggy Overberg 1 , Inga Rose 1 , Gargi D. Basu 1 , Semir Vranic 3 , Henry T. Lynch 2 , Daniel D. Von Hoff 4 , and Omid Hamid 5 Abstract Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facil- itating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1–positive tumor-infiltrating lymphocytes (TIL) and cancer cells’ expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1 þ TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P ¼ 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro- and liposarcomas), but showed the inverse association with the number of detected mutations (P ¼ 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the micro- satellite stable tumors (P ¼ 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P ¼ 0.002). In non–small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities. Cancer Epidemiol Biomarkers Prev; 23(12); 2965–70. Ó2014 AACR. Introduction Programmed death-1 (PD-1, CD279) is an immune- suppressive molecule that is upregulated on activated T cells and other immune cells. It is activated by binding to its ligand PD-L1 (B7-H1, CD274), which results in intra- cellular responses that reduce T-cell activation. Aberrant PD-L1 expression had been observed on cancer cells, leading to the development of PD-1/PD-L1–directed can- cer therapies, which have shown promising results in late- phase clinical trials. Blockade of the PD-1 and PD-L1 interaction led to good clinical responses in several, but not all cancer types, and the heterogeneous cellular expression of PD-1/PD-L1 may underlie these selective responses (1–6). PD-1/PD-L1 expression has been studied by various methods in different cancer subtypes (7). Most of the published articles focused on prognostic relevance of PD-1/PD-L1, whereas little is known about their predic- tive value as well as their relationship with molecular genetic alterations in solid tumors (1). In the present study, we analyzed the distribution of PD-1 þ tumor- infiltrating lymphocytes (TIL) and PD-L1 expression in the most common solid cancers and further correlated these biomarkers with genotypic and phenotypic charac- teristics of tumors. Materials and Methods Tumor samples The study cohort consisted of 437 tumor samples (both primary and metastatic) representing both major and some rare solid cancer types: 380 carcinomas [breast, colon, lung, pancreas, prostate, Merkel cell, ovary, liver, 1 Caris Life Sciences, Phoenix, Arizona. 2 Department of Preventive Med- icine and Public Health, Creighton University, Omaha, Nebraska. 3 Depart- ment of Pathology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina. 4 Translational Genomic Research Institute and Virginia G. Piper Cancer Center, Phoenix, Arizona. 5 The Angeles Clinic and Research Institute, Los Angeles, California. Corresponding Author: Zoran Gatalica, Caris Life Sciences, 4610 South, 44th Place, Phoenix, AZ 85040. Phone: 602-464-7536; Fax: 602-464-7661; E-mail: zgatalica@carisls.com doi: 10.1158/1055-9965.EPI-14-0654 Ó2014 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention www.aacrjournals.org 2965 on June 19, 2020. © 2014 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst November 12, 2014; DOI: 10.1158/1055-9965.EPI-14-0654