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

• Published in: Cancers Vol. 12; no. 7; p. 1943
• Main Authors: Amato, Carol M, Hintzsche, Jennifer D, Wells, Keith, Applegate, Allison, Gorden, Nicholas T, Vorwald, Victoria M, Tobin, Richard P, Nassar, Kelsey, Shellman, Yiqun G, Kim, Jihye, Medina, Theresa M, Rioth, Matthew, Lewis, Karl D, McCarter, Martin D, Gonzalez, Rene, Tan, Aik-Choon, Robinson, William A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17-07-2020; MDPI
• Subjects: Cancer therapies; CD83 antigen; Codons; Consent; Deoxyribonucleic acid; DNA; Flow cytometry; Gene expression; Gene set enrichment analysis; Genomics; Immunotherapy; Library collections; Melanoma; Metastases; Metastasis; Mutation; NF-κB protein; Patients; PD-1 protein; Ribonucleic acid; RNA; Signal transduction; Tumor cells; Tumors; United States > US; Colorado; RNA sequencing; CD83; immunotherapy; melanoma; NFKB; anti-PD1; biomarker; whole exome sequencing
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12071943

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
, a negative regulator of
, were found exclusively in the responders. Mutations in
-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored
-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
signaling via
pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro
activity assays indicated that the G34E variant caused loss-of-function of
, and resulted in activation of
signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that
activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in
-related genes should be considered.