scholarly journals The Evolving Landscape of Biomarkers for Anti-PD-1 or Anti-PD-L1 Therapy

2019 ◽  
Vol 8 (10) ◽  
pp. 1534 ◽  
Author(s):  
Antje Tunger ◽  
Ulrich Sommer ◽  
Rebekka Wehner ◽  
Anne Sophie Kubasch ◽  
Marc-Oliver Grimm ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Tumor Regression ◽  
Treatment Resistance ◽  
Immune Monitoring ◽  
Small Cell Lung ◽  
Tumor Patients ◽  
Programmed Cell Death 1 ◽  
Promising Treatment ◽  
Cell Death Protein

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4+ and CD8+ T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy.

scholarly journals Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer

2020 ◽  
Vol 52 (9) ◽  
pp. 1550-1563
Author(s):  
Jae-Won Cho ◽  
Min Hee Hong ◽  
Sang-Jun Ha ◽  
Young-Joon Kim ◽  
Byoung Chul Cho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Regulatory Elements ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cpg Sites ◽  
Cell Death Protein

Abstract Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.

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