Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis.
METHODS: The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining.
RESULTS: We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM.
CONCLUSIONS: PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 11(2023), 1 vom: 21. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dai, Jie [VerfasserIn] |
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| Links: |
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| Themen: |
Genetic Markers |
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| Anmerkungen: |
Date Completed 04.01.2023 Date Revised 13.12.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2022-005937 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
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| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a BACKGROUND: Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis | ||
| 520 | |a METHODS: The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining | ||
| 520 | |a RESULTS: We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM | ||
| 520 | |a CONCLUSIONS: PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Genetic Markers | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Melanoma | |
| 650 | 4 | |a Programmed Cell Death 1 Receptor | |
| 650 | 4 | |a Tumor Microenvironment | |
| 700 | 1 | |a Bai, Xue |e verfasserin |4 aut | |
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| 700 | 1 | |a Wei, Xiaoting |e verfasserin |4 aut | |
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| 700 | 1 | |a Si, Lu |e verfasserin |4 aut | |
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