دورية
Evolution of delayed resistance to immunotherapy in a melanoma responder
| العنوان: | Evolution of delayed resistance to immunotherapy in a melanoma responder |
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| المؤلفون: | 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. |
| المصدر: | Nature Medicine; 20210101, Issue: Preprints p1-8, 8p |
| مستخلص: | Despite initial responses1–3, most melanoma patients develop resistance4to 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 NGFRhitumor 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 10788956 1546170X |
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| DOI: | 10.1038/s41591-021-01331-8 |