Cargando…
Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome
While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades,...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9393646/ https://www.ncbi.nlm.nih.gov/pubmed/36003398 http://dx.doi.org/10.3389/fimmu.2022.979993 |
_version_ | 1784771314438897664 |
---|---|
author | Attrill, Grace H. Lee, Hansol Tasker, Annie T. Adegoke, Nurudeen A. Ferguson, Angela L. da Silva, Ines Pires Saw, Robyn P. M. Thompson, John F. Palendira, Umaimainthan Long, Georgina V. Ferguson, Peter M. Scolyer, Richard A. Wilmott, James S. |
author_facet | Attrill, Grace H. Lee, Hansol Tasker, Annie T. Adegoke, Nurudeen A. Ferguson, Angela L. da Silva, Ines Pires Saw, Robyn P. M. Thompson, John F. Palendira, Umaimainthan Long, Georgina V. Ferguson, Peter M. Scolyer, Richard A. Wilmott, James S. |
author_sort | Attrill, Grace H. |
collection | PubMed |
description | While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis. |
format | Online Article Text |
id | pubmed-9393646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93936462022-08-23 Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome Attrill, Grace H. Lee, Hansol Tasker, Annie T. Adegoke, Nurudeen A. Ferguson, Angela L. da Silva, Ines Pires Saw, Robyn P. M. Thompson, John F. Palendira, Umaimainthan Long, Georgina V. Ferguson, Peter M. Scolyer, Richard A. Wilmott, James S. Front Immunol Immunology While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis. Frontiers Media S.A. 2022-08-08 /pmc/articles/PMC9393646/ /pubmed/36003398 http://dx.doi.org/10.3389/fimmu.2022.979993 Text en Copyright © 2022 Attrill, Lee, Tasker, Adegoke, Ferguson, da Silva, Saw, Thompson, Palendira, Long, Ferguson, Scolyer and Wilmott https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Attrill, Grace H. Lee, Hansol Tasker, Annie T. Adegoke, Nurudeen A. Ferguson, Angela L. da Silva, Ines Pires Saw, Robyn P. M. Thompson, John F. Palendira, Umaimainthan Long, Georgina V. Ferguson, Peter M. Scolyer, Richard A. Wilmott, James S. Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title | Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title_full | Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title_fullStr | Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title_full_unstemmed | Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title_short | Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
title_sort | detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9393646/ https://www.ncbi.nlm.nih.gov/pubmed/36003398 http://dx.doi.org/10.3389/fimmu.2022.979993 |
work_keys_str_mv | AT attrillgraceh detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT leehansol detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT taskeranniet detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT adegokenurudeena detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT fergusonangelal detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT dasilvainespires detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT sawrobynpm detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT thompsonjohnf detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT palendiraumaimainthan detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT longgeorginav detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT fergusonpeterm detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT scolyerricharda detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome AT wilmottjamess detailedspatialimmunophenotypingofprimarymelanomasrevealsimmunecellsubpopulationsassociatedwithpatientoutcome |