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Article

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

1
Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA
2
Willamette Valley Cancer Institute and Research Center, Corvallis, OR 97330, USA
3
Saint Alphonsus Cancer Institute, Boise, ID 83706, USA
4
Department of Surgery, Division of Surgical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA
5
Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA
6
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1943; https://doi.org/10.3390/cancers12071943
Received: 30 May 2020 / Revised: 13 July 2020 / Accepted: 13 July 2020 / Published: 17 July 2020
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. View Full-Text
Keywords: immunotherapy; whole exome sequencing; melanoma; RNA sequencing; biomarker; anti-PD1; NFKB; CD83 immunotherapy; whole exome sequencing; melanoma; RNA sequencing; biomarker; anti-PD1; NFKB; CD83
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MDPI and ACS Style

Amato, C.M.; Hintzsche, J.D.; Wells, K.; Applegate, A.; Gorden, N.T.; Vorwald, V.M.; Tobin, R.P.; Nassar, K.; Shellman, Y.G.; Kim, J.; Medina, T.M.; Rioth, M.; Lewis, K.D.; McCarter, M.D.; Gonzalez, R.; Tan, A.-C.; Robinson, W.A. Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy. Cancers 2020, 12, 1943. https://doi.org/10.3390/cancers12071943

AMA Style

Amato CM, Hintzsche JD, Wells K, Applegate A, Gorden NT, Vorwald VM, Tobin RP, Nassar K, Shellman YG, Kim J, Medina TM, Rioth M, Lewis KD, McCarter MD, Gonzalez R, Tan A-C, Robinson WA. Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy. Cancers. 2020; 12(7):1943. https://doi.org/10.3390/cancers12071943

Chicago/Turabian Style

Amato, Carol M., Jennifer D. Hintzsche, Keith Wells, Allison Applegate, Nicholas T. Gorden, Victoria M. Vorwald, Richard P. Tobin, Kelsey Nassar, Yiqun G. Shellman, Jihye Kim, Theresa M. Medina, Matthew Rioth, Karl D. Lewis, Martin D. McCarter, Rene Gonzalez, Aik-Choon Tan, and William A. Robinson 2020. "Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy" Cancers 12, no. 7: 1943. https://doi.org/10.3390/cancers12071943

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