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 recurre...
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/143713 |
| _version_ | 1811090229599141888 |
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| author | Kellis, Manolis |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Kellis, Manolis |
| author_sort | Kellis, Manolis |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:39:09Z |
| format | Article |
| id | mit-1721.1/143713 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:39:09Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1437132023-04-13T20:38:04Z Evolution of delayed resistance to immunotherapy in a melanoma responder Kellis, Manolis Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory 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. 2022-07-13T16:27:36Z 2022-07-13T16:27:36Z 2021 2022-07-13T16:20:20Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/143713 Kellis, Manolis. 2021. "Evolution of delayed resistance to immunotherapy in a melanoma responder." Nature Medicine, 27 (6). en 10.1038/S41591-021-01331-8 Nature Medicine 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. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Kellis, Manolis Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title | Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title_full | Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title_fullStr | Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title_full_unstemmed | Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title_short | Evolution of delayed resistance to immunotherapy in a melanoma responder |
| title_sort | evolution of delayed resistance to immunotherapy in a melanoma responder |
| url | https://hdl.handle.net/1721.1/143713 |
| work_keys_str_mv | AT kellismanolis evolutionofdelayedresistancetoimmunotherapyinamelanomaresponder |