Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy
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 lesion...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005937.full |
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| author | Yu Chen Xuan Wang Jie Dai Li Zhou Xuefeng Xia Jun Guo Xue Bai Lu Si Bixia Tang Chuanliang Cui Xiaoting Wei Xinan Sheng Siming Li Zhihong Chi Lili Mao Bin Lian Xieqiao Yan Yan Kong Caili Li Xuan Gao Lirui Tang Linzi Sun Zhonghui Qi Zelong Xu |
| author_facet | Yu Chen Xuan Wang Jie Dai Li Zhou Xuefeng Xia Jun Guo Xue Bai Lu Si Bixia Tang Chuanliang Cui Xiaoting Wei Xinan Sheng Siming Li Zhihong Chi Lili Mao Bin Lian Xieqiao Yan Yan Kong Caili Li Xuan Gao Lirui Tang Linzi Sun Zhonghui Qi Zelong Xu |
| author_sort | Yu Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ef571d10c780498bb9695650403c1b6b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ef571d10c780498bb9695650403c1b6b2025-01-29T11:15:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005937Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapyYu Chen0Xuan Wang1Jie Dai2Li Zhou3Xuefeng Xia4Jun Guo5Xue Bai6Lu Si7Bixia Tang8Chuanliang Cui9Xiaoting Wei10Xinan Sheng11Siming Li12Zhihong Chi13Lili Mao14Bin Lian15Xieqiao Yan16Yan Kong17Caili Li18Xuan Gao19Lirui Tang20Linzi Sun21Zhonghui Qi22Zelong Xu232 Department of Infectious Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China1 Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USAKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaEikon Therapeutics, Inc., Hayward, CA, USAGeneplus-Beijing, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaDepartment of Radiotherapy, The Second Affiliated Hospital of Guilin Medical University, Guilin, China1Peking University Cancer Hospital and Institute, Beijing, ChinaPeking University Cancer Hospital & Institute, Beijing, ChinaPeking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Obstetrics and Gynecology, Peking University People`s Hospital, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaPeking University Cancer Hospital & Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, China1Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, ChinaGeneplus-Beijing, Beijing, ChinaBackground 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.https://jitc.bmj.com/content/11/1/e005937.full |
| spellingShingle | Yu Chen Xuan Wang Jie Dai Li Zhou Xuefeng Xia Jun Guo Xue Bai Lu Si Bixia Tang Chuanliang Cui Xiaoting Wei Xinan Sheng Siming Li Zhihong Chi Lili Mao Bin Lian Xieqiao Yan Yan Kong Caili Li Xuan Gao Lirui Tang Linzi Sun Zhonghui Qi Zelong Xu Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy Journal for ImmunoTherapy of Cancer |
| title | Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
| title_full | Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
| title_fullStr | Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
| title_full_unstemmed | Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
| title_short | Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy |
| title_sort | molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti pd 1 monotherapy |
| url | https://jitc.bmj.com/content/11/1/e005937.full |
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