BioProject

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. More...

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 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 the TNFalpha signaling via NFkB pathway as one of the top pathways with differential expression in responders vs non-responders, including CD83 which was highly expressed in our responder group. In vitro NFkB activity assays indicated that the G34E variant causes loss-of-function of NFKBIE. Thus, G34E variant can result in activation of NFkB signaling and associated upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered. Less...