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| Status |
Public on Aug 07, 2020 |
| Title |
Pre- Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma; However, predicting which patients will respond to immunotherapy is still unknown. 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 NF-kB, were found exclusively in the responders. NKBIE-related genes within the responder group were also enriched 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 subsection of tumor samples identified differential expression of the TNFA signaling via NFKB pathway, which includes CD83. By overexpressing NFKBIEG34E we were able to demonstrate this mutation is related to increased NF-kB activity, including increased CD83 protein expression when compared with the wildtype. These results suggest that increased NF-kB signaling as a consequence of an NFKBIE mutation may contribute to a favorable anti-PD1 treatment response, including a possible novel role of CD83 in solid tumors.
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| Overall design |
We analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. RNA sequencing on a subsection of tumor samples identified differential expression of the TNFA signaling via NFKB pathway, which includes CD83
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| Contributor(s) |
Amato CM, Wells K, Hintzsche JD, Applegate A, Gordon N, Vorwald VM, Tobin RP, Nassar K, Kim J, Shellman Y, Medina T, Rioth M, Lewis K, McCarter MD, Tan A, Robinson WA |
| Citation(s) |
32708981 |
| Submission date |
Feb 26, 2020 |
| Last update date |
Nov 06, 2020 |
| Contact name |
Jihye Kim |
| E-mail(s) |
kim.jihey@gmail.com
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| Phone |
7209755448
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| Organization name |
Cleveland Clinic
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| Department |
Quantitative Health Sciences
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| Street address |
9500 Euclid Ave.
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| City |
Cleveland |
| State/province |
Ohio |
| ZIP/Postal code |
44195 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (14)
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| Relations |
| BioProject |
PRJNA608935 |
| SRA |
SRP250849 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE145996_Melanoma_Immune_FPKM.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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