Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy.

Autor: Amato CM; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Hintzsche JD; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Wells K; Willamette Valley Cancer Institute and Research Center, Corvallis, OR 97330, USA., Applegate A; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Gorden NT; Saint Alphonsus Cancer Institute, Boise, ID 83706, USA., Vorwald VM; Department of Surgery, Division of Surgical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Tobin RP; Department of Surgery, Division of Surgical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Nassar K; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Shellman YG; Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Kim J; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Medina TM; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Rioth M; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Lewis KD; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., McCarter MD; Department of Surgery, Division of Surgical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Gonzalez R; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA., Tan AC; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA., Robinson WA; Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2020 Jul 17; Vol. 12 (7). Date of Electronic Publication: 2020 Jul 17.
DOI: 10.3390/cancers12071943
Abstrakt: Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE , a negative regulator of NFkB , were found exclusively in the responders. Mutations in NKBIE -related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE -related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE , and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB -related genes should be considered.
Databáze: MEDLINE
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