Liu, DavidLin, Jia-RenRobitschek, EmilyKasumova, GyulnaraHeyde, AlexanderShi, AlvinKraya, AdamZhang, GaoMoll, TabeaFrederick, DennieChen, Yu-AnSchapiro, DenisHo, Li-LunBi, KevinSahu, AvinashMei, ShaolinMiao, BenchunSharova, TatyanaAlvarez-Breckenridge, ChristopherStocking, JacksonKim, TommyFadden, RileyLawrence, DonaldHoang, MaiCahill, DanielMaleh Mir, MohsenNowak, MartinBrastianos, PriscillaLian, ChristineRuppin, EytanIzar, BenjaminHerlyn, MeenhardVan Allen, EliezerNathanson, KatherineFlaherty, KeithSullivan, RyanKellis, ManolisSorger, PeterBoland, Genevieve2023-06-292021-05-03Liu, David, Jia-Ren Lin, Emily J Robitschek, Gyulnara G Kasumova, Alex Heyde, Alvin Shi, Adam Kraya, et al. 2021. “Evolution of Delayed Resistance to Immunotherapy in a Melanoma Responder.” Nature Medicine 27 (6): 985–92.https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376302Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a metastatic melanoma patient with exceptional response followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of 7 lineages with multiple convergent, but independent resistance-associated alterations (RAAs). 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 RNAseq and highly-multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition amongst different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR-High tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated 2 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 melanoma patient with an unusual clinical course.en-USJournal Article2023-06-2910.1038/s41591-021-01331-8