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Association of PD-1/PD-L Axis Expression with Cytolytic Activity

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Association of PD-1/PD-L Axis Expression with Cytolytic Activity Association of PD-1/PD-L axis expression with cytolytic PNAS PLUS activity, mutational load, and prognosis in melanoma and other solid tumors Ludmila Danilovaa,b,c, Hao Wanga, Joel Sunshined, Genevieve J. Kaunitzd, Tricia R. Cottrelle, Haiying Xud, Jessica Esandriod, Robert A. Andersa,c,e, Leslie Copea,c, Drew M. Pardolla,c, Charles G. Drakea,c,f, and Janis M. Taubea,c,d,e,1 aDepartment of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; bVavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia, 119333; cThe Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; dDepartment of Dermatology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; eDepartment of Pathology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; and fThe Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 Edited by Antoni Ribas, Ronald Reagan University of California, Los Angeles Medical Center, Los Angeles, CA, and accepted by Editorial Board Member Tak W. Mak October 8, 2016 (received for review June 3, 2016) Programmed cell death protein-1 (PD-1)/programmed death ligand-1 infiltration and improved overall patient survival (14). Mutational (PD-L1) checkpoint blockade has led to remarkable and durable burden has also recently been demonstrated to predict response to objective responses in a number of different tumor types. A better anti–PD-1 therapy in patients with nonsmall cell lung carcinoma understanding of factors associated with the PD-1/PD-L axis expres- (NSCLC) (15). sion is desirable, as it informs their potential role as prognostic and PD-L1 expression in the pretreatment tumor microenviron- predictive biomarkers and may suggest rational treatment combi- ment has also been shown to predict response to PD-1/PD-L1 nations. In the current study, we analyzed PD-L1, PD-L2, PD-1,and blockade in multiple tumor types (8, 16–19). However, in con- cytolytic activity (CYT) expression, as well as mutational density trast to CD8, PD-L1 expression has been ascribed ambivalent from melanoma and eight other solid tumor types using The Cancer prognostic significance. It has been correlated with decreased Genome Atlas database. We found that in some tumor types, PD-L2 survival in esophageal, gastric, ovarian, pancreatic, and renal cell expression is more closely linked to Th1/IFNG expression and PD-1 carcinomas (20–25), and has been associated with an improved and CD8 signaling than PD-L1. In contrast, mutational load was not survival in patients with Merkel cell (26), breast (27), and cer- Th1/IFNG PD-L1 correlated with a gene signature in any tumor type. , vical carcinomas (28). Conflicting reports also exist regarding its PD-L2 PD-1 CYT , , expression, and mutational density are all positive significance within the same tumor type (e.g., melanoma and prognostic features in melanoma, and conditional inference model- NSCLC) (6, 29–31). These differences may be attributed to the ing revealed PD-1/CYT expression (i.e., an inflamed tumor microen- vironment) as the most impactful feature, followed by mutational Significance density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti– PD-1/PD-L1 will benefit from tumor-type–specific, integrated, mRNA, The Cancer Genome Atlas datasets were used in the current study PD-L1 protein, and genomic approaches. to explore the relationship of programmed death ligand-1 ( ) expression, a cytotoxic T-cell gene signature, and mutational load PD-1 | PD-L1 | PD-L2 | melanoma | mutational load to each other, to immunoactive factors, such as programmed cell death protein-1 (PD-1), PD-L2, and other checkpoint molecules, – and to survival across multiple solid tumor types. We found that he host tumor interaction represents a complex, layered in- PD-L2 expression is more closely related to an ongoing host im- Tterplay of competing factors, the balance of which ultimately mune response in certain tumor types than PD-L1.Notably,mu- impacts patient survival. Genomic instability gives rise to muta- tational load was not immediately related to inflammation in any tions, facilitating tumor progression (1). At the same time, such tumor type studied, and was inferior to an inflamed tumor mi- mutations generate neoepitopes that may be recognized by the + croenvironment for predicting survival in patients with metastatic adaptive immune system, eliciting a protective, CD8 T-cell– – melanoma. Our findings also indicate the need for biomarker mediated antitumor response (2 5). In the next tier of interaction, assays that are tumor-type–specific and include both expression the tumor may demonstrate programmed death ligand-1 (PD- studies and genomic profiling. L1)–mediated adaptive immune resistance, effectively turning off the surveilling T-cells via the programmed cell death protein-1 Author contributions: L.D., H.W., L.C., D.M.P., C.G.D., and J.M.T. designed research; L.D., (PD-1)/PD-L1 axis (6). Agents blocking either PD-1 or PD-L1 H.W., H.X., J.E., and J.M.T. performed research; L.D., H.W., J.S., G.J.K., T.R.C., R.A.A., L.C., prevent this last interaction, allowing an unbridled host response C.G.D., and J.M.T. analyzed data; and L.D., H.W., J.S., G.J.K., T.R.C., H.X., J.E., R.A.A., L.C., to tumor and potentially tipping the balance in favor of improved D.M.P., C.G.D., and J.M.T. wrote the paper. patient survival (7–9). Conflict of interest statement: R.A.A. is a compensated consultant for Adaptive Biotech. Factors at each of these levels have been highlighted as both D.M.P. has received research grants from Bristol-Myers Squibb and Potenza Therapeutics; + consults for Amgen, Five Prime Therapeutics, GlaxoSmithKline, Jounce Therapeutics, prognostic and predictive. The impact of CD8 T-cell infiltration on MedImmune, Merck, Pfizer, Potenza Therapeutics, and Sanofi; owns stock options in survival has been the most well-studied. One meta-analysis sum- Jounce and Potenza; and receives patent royalties through his institution, from Bristol- INFLAMMATION + Myers Squibb, and Potenza. C.G.D. is a self-compensated consultant for Bristol-Myers IMMUNOLOGY AND marized that in 58 of 60 articles published, CD8 immune cell in- Squibb, AstraZeneca/Medimmune, Roche/Genentech, Potenza Therapeutics, and Tizona filtrates were a good prognostic feature in a wide variety of solid Therapeutics; and has patents licensed by Bristol-Myers Squibb, AstraZeneca/Medi- + tumor types (10). CD8 T-cell infiltration has also been associated mmune, and Potenza Therapeutics. J.M.T. is a compensated consultant for Bristol-Myers Squibb, AstraZeneca/Medimmune, and Merck. with an improved response to chemotherapy (11, 12), neoadjuvant – This article is a PNAS Direct Submission. A.R. is a Guest Editor invited by the Editorial therapy (13), and most recently, to anti PD-1 immunotherapy (8). Board. Similarly, immunogenic mutations in six solid tumor types (lung, 1To whom correspondence should be addressed. Email: [email protected]. ovary, breast, colorectal, brain, and kidney cancer in combined + This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. analysis) were recently shown to correlate with both CD8 T-cell 1073/pnas.1607836113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1607836113 PNAS | Published online November 11, 2016 | E7769–E7777 Downloaded by guest on October 1, 2021 different detection and scoring systems used to quantify PD-L1 kidney renal clear cell carcinoma; LUSC, squamous cell carci- expression, variations in sample size, and variable follow-up du- noma of the lung; LUAD, lung adenocarcinoma; COAD, colonic ration. The mechanisms underlying PD-L1 expression—for exam- adenocarcinoma; HNSC, head and neck squamous cell carci- ple, an adaptive (IFN-γ–mediated) vs. an intrinsic pattern (because noma; PAAD, pancreatic adenocarcinoma; BRCA, breast car- of oncogenic driver mutations, loss of tumor suppressor genes, or cinoma; BLCA, bladder carcinoma), we determined the relative PD-L gene amplification)—may also influence the impact of PD- expression levels of PD-L1 (CD274), PD-L2 (PDCD1LG2), PD-1 L1 expression on survival as well as its utility as a biomarker for (PDCD1), and CYT (combined GZMA_PRF1 transcript levels, response to anti–PD-1/L1 therapy. The second ligand for PD-1, indicating cytolytic effector activity) (5). All cohorts were pri- PD-L2, is not as well-explored as PD-L1; that is, possible adaptive mary tumors, except for SKCM, where only metastases were vs. innate mechanisms of PD-L2 expression, its relationship to studied because of available sample numbers. Importantly, me- other markers of the PD-1/PD-L axis, and the prognostic signifi- dian levels of PD-Ls, PD-1, and CYT expression did not vary cance of PD-L2 have yet to be broadly and systematically significantly between primary or metastases, or by metastatic site addressed(21,23,25,28,32,33).Studiesataproteinlevelhave for SKCM (Fig. S1). Innate mechanisms of PD-L1 expression likely been limited because of the lack of a reliable, commercially have also been described, including amplifications of the PD-L available anti–PD-L2 antibody. Studies focused on the prognostic genes and mutations in tumor suppressor genes (36–39). We and predictive value of PD-1 in the tumor microenvironment are found that genetic alterations in the PD-Ls themselves occur on also more limited (8, 18, 25, 34, 35). average in <5% of tumor types studied, and that these alter- The purpose of this study was to use The Cancer Genome Atlas ations did not lead to statistically different levels of gene ex- (TCGA) dataset to determine the relationship between cytotoxic pression or altered survival compared with patients lacking such T-cells, PD-1/PD-L axis molecules, and mutational load, and their alterations (Fig.
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