Evolution of delayed resistance to immunotherapy in a melanoma responder.
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.
Liu, D; Lin, J-R; Robitschek, EJ; Kasumova, GG; Heyde, A; Shi, A; Kraya, A; Zhang, G; Moll, T; Frederick, DT; Chen, Y-A; Wang, S; Schapiro, D; Ho, L-L; Bi, K; Sahu, A; Mei, S; Miao, B; Sharova, T; Alvarez-Breckenridge, C; Stocking, JH; Kim, T; Fadden, R; Lawrence, D; Hoang, MP; Cahill, DP; Malehmir, M; Nowak, MA; Brastianos, PK; Lian, CG; Ruppin, E; Izar, B; Herlyn, M; Van Allen, EM; Nathanson, K; Flaherty, KT; Sullivan, RJ; Kellis, M; Sorger, PK; Boland, GM
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