Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas
Background While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined ch...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| author | Jin Xu Andrew Knight Jonathan Nguyen Hong Wang Walter J Storkus Cindy Sander John M Kirkwood Jiqiang Yao Xiaofei Song Jane Messina James J Mulé Lilit Karapetyan Carlos Moran-Segura Aofei Li Marion Joy Sabrina Bruno Hassan M Abushukair Danielle Vargas De Stefano Ayah N Al-Bzour Caroline Layding |
| author_facet | Jin Xu Andrew Knight Jonathan Nguyen Hong Wang Walter J Storkus Cindy Sander John M Kirkwood Jiqiang Yao Xiaofei Song Jane Messina James J Mulé Lilit Karapetyan Carlos Moran-Segura Aofei Li Marion Joy Sabrina Bruno Hassan M Abushukair Danielle Vargas De Stefano Ayah N Al-Bzour Caroline Layding |
| author_sort | Jin Xu |
| collection | DOAJ |
| description | Background While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma.Methods We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas.Results A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20+ (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4+ and CD8+ T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p<0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01).Conclusion Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease. |
| format | Article |
| id | doaj-art-f6e6ee07f4b146a0b9b6969deec7591c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f6e6ee07f4b146a0b9b6969deec7591c2024-11-14T05:55:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-009231Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomasJin Xu0Andrew Knight1Jonathan Nguyen2Hong Wang3Walter J Storkus4Cindy Sander5John M Kirkwood6Jiqiang Yao7Xiaofei Song8Jane Messina9James J Mulé10Lilit Karapetyan11Carlos Moran-Segura12Aofei Li13Marion Joy14Sabrina Bruno15Hassan M Abushukair16Danielle Vargas De Stefano17Ayah N Al-Bzour18Caroline Layding1911 Moffitt Cancer Center, Tampa, Florida, USA9 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA13 Pathology, H Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA10 Graduate School of Public Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA17 Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA15 UPMC, Pittsburgh, Pennsylvania, USA19 Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA11 Moffitt Cancer Center, Tampa, Florida, USA11 Moffitt Cancer Center, Tampa, Florida, USA16 Department of Pathology, Moffitt Cancer Center, Tampa, Florida, USA11 Moffitt Cancer Center, Tampa, Florida, USA1 Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA13 Pathology, H Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA2 Department of Pathology, Indiana University, Indianapolis, Indiana, USA5 University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA14 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA6 Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan4 Department of Pathology, Phoenix Children`s Hospital, Phoenix, Arizona, USA6 Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan3 UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USABackground While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma.Methods We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas.Results A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20+ (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4+ and CD8+ T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p<0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01).Conclusion Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease.https://jitc.bmj.com/content/12/11/e009231.full |
| spellingShingle | Jin Xu Andrew Knight Jonathan Nguyen Hong Wang Walter J Storkus Cindy Sander John M Kirkwood Jiqiang Yao Xiaofei Song Jane Messina James J Mulé Lilit Karapetyan Carlos Moran-Segura Aofei Li Marion Joy Sabrina Bruno Hassan M Abushukair Danielle Vargas De Stefano Ayah N Al-Bzour Caroline Layding Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas Journal for ImmunoTherapy of Cancer |
| title | Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| title_full | Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| title_fullStr | Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| title_full_unstemmed | Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| title_short | Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| title_sort | differences in the pathological transcriptomic and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas |
| url | https://jitc.bmj.com/content/12/11/e009231.full |
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