Dataset Information

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

ABSTRACT: Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.

SUBMITTER: Rabbie R

PROVIDER: S-EPMC7453196 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Rabbie Roy R Ansari-Pour Naser N Cast Oliver O Lau Doreen D Scott Francis F Welsh Sarah J SJ Parkinson Christine C Khoja Leila L Moore Luiza L Tullett Mark M Wong Kim K Ferreira Ingrid I Gómez Julia M Martínez JMM Levesque Mitchell M Gallagher Ferdia A FA Jiménez-Sánchez Alejandro A Riva Laura L Miller Martin L ML Allinson Kieren K Campbell Peter J PJ Corrie Pippa P Wedge David C DC Adams David J DJ

Nature communications 20200827 1

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branche ...[more]

PMID: 32855398

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Project description:BACKGROUND:Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model. METHODS:B78 (GD2+) melanoma 'primary' tumors were engrafted on the right flank of C57BL/6 mice. After 3-4 weeks, primary tumors were treated with ISV (radiation (12?Gy, day 1), ?-GD2 immunocytokine (hu14.18-IL2, days 6-10)) and ICI (?-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay. RESULTS:ISV+?-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+?-CTLA-4 increased survival compared with ICI alone. ISV+?-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+?-CTLA-4 increased CD8+ and CD4+ T cells in flank and brain tumors compared with untreated mice. Among ISV + ?-CTLA-4 treated mice, left flank tumors showed increased CD8+ infiltration and CD8+:FOXP3+ ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or Mhc-1. Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+?-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts. CONCLUSION:ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+?-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.

Dataset Information

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Publications

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

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