Evolution of delayed resistance to immunotherapy in a melanoma responder
Name
nihms-1728970.pdf
Description
Accepted version
Size
4.34 MB
Format
Adobe PDF
Checksum (MD5)
60d1aeacb98cf48a50c075312e6854ea
Author(s)
Kellis, Manolis
Date Issued
2021
Journal
Nature Medicine
Publisher
Springer Science and Business Media LLC
Citation
Kellis, Manolis. 2021. "Evolution of delayed resistance to immunotherapy in a melanoma responder." Nature Medicine, 27 (6).
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/S41591-021-01331-8
