Evolution of delayed resistance to immunotherapy in a melanoma responder.
IF: 87.241
Cited by: 48


Despite initial responses1-3, most melanoma patients develop resistance4 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 NGFRhi 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.



MeSH terms

B7-H1 Antigen
Chromosomes, Human, Pair 15
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Immune Checkpoint Inhibitors
Neoplasm Metastasis
Neoplasm Recurrence, Local
Nerve Tissue Proteins
Receptors, Nerve Growth Factor
Tumor Microenvironment


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

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