TY - JOUR
T1 - Evolution of delayed resistance to immunotherapy in a melanoma responder
AU - Liu, David
AU - Lin, Jia Ren
AU - Robitschek, Emily J.
AU - Kasumova, Gyulnara G.
AU - Heyde, Alex
AU - Shi, Alvin
AU - Kraya, Adam
AU - Zhang, Gao
AU - Moll, Tabea
AU - Frederick, Dennie T.
AU - Chen, Yu An
AU - Wang, Shu
AU - Schapiro, Denis
AU - Ho, Li Lun
AU - Bi, Kevin
AU - Sahu, Avinash
AU - Mei, Shaolin
AU - Miao, Benchun
AU - Sharova, Tatyana
AU - Alvarez-Breckenridge, Christopher
AU - Stocking, Jackson H.
AU - Kim, Tommy
AU - Fadden, Riley
AU - Lawrence, Donald
AU - Hoang, Mai P.
AU - Cahill, Daniel P.
AU - Malehmir, Mohsen
AU - Nowak, Martin A.
AU - Brastianos, Priscilla K.
AU - Lian, Christine G.
AU - Ruppin, Eytan
AU - Izar, Benjamin
AU - Herlyn, Meenhard
AU - Van Allen, Eliezer M.
AU - Nathanson, Katherine
AU - Flaherty, Keith T.
AU - Sullivan, Ryan J.
AU - Kellis, Manolis
AU - Sorger, Peter K.
AU - Boland, Genevieve M.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105326395&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01331-8
DO - 10.1038/s41591-021-01331-8
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C2 - 33941922
AN - SCOPUS:85105326395
SN - 1078-8956
VL - 27
SP - 985
EP - 992
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -
