Journal Article

Evolution of delayed resistance to immunotherapy in a melanoma responder

Sullivan, Ryan J., Shi, Alvin, Liu, David, Heyde, Alex, Flaherty, Keith T., Ho, Li-Lun, Ruppin, Eytan, Mei, Shaolin, Malehmir, Mohsen, Miao, Benchun, Kellis, Manolis, Sahu, Avinash, Bi, Kevin, Herlyn, Meenhard, Kraya, Adam, Moll, Tabea, Kasumova, Gyulnara G., Van Allen, Eliezer M., Lin, Jia-Ren, Sorger, Peter K., Chen, Yu-An, Zhang, Gao, Stocking, Jackson H., Wang, Shu, Cahill, Daniel P., Kim, Tommy, Nathanson, Katherine, Sharova, Tatyana, Boland, Genevieve M., Schapiro, Denis, Robitschek, Emily J., Lian, Christine G., Hoang, Mai P., Frederick, Dennie T., Nowak, Martin A., Izar, Benjamin, Fadden, Riley, Lawrence, Donald, Brastianos, Priscilla K., Alvarez-Breckenridge, Christopher

2021

Overview

Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR hi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor–immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course. Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059/2325 / 631/67/1059/2326 / 631/67/1813/1634 / 631/67/69 / Autopsies / Autopsy / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromosome 15 / Chromosomes, Human, Pair 15 - genetics / Coevolution / Drug Resistance, Neoplasm - drug effects / Evolution / Female / Gene Expression Regulation, Neoplastic / Gene sequencing / Genetic analysis / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - therapeutic use / Immune system / Immunofluorescence / Immunotherapy / Immunotherapy - adverse effects / Infectious Diseases / Letter / Lung cancer / Male / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Metabolic Diseases / Metastases / Microenvironments / Mimicry / Molecular Medicine / Neoplasm Metastasis / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - immunology / Neoplasm Recurrence, Local - pathology / Neoplasm Recurrence, Local - therapy / Nerve growth factor receptors / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - immunology / Neurosciences / Patients / PD-L1 protein / Phenotypes / Phylogeny / Polarity / Receptors, Nerve Growth Factor - genetics / Receptors, Nerve Growth Factor - immunology / Treatment resistance / Tumor cells / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumors