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Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome
BACKGROUND: Immune checkpoint inhibitors (ICI) can lead to long-term responses in patients with metastatic melanoma. Still many patients with melanoma are intrinsically resistant or acquire secondary resistance. Previous studies have used primary or metastatic tumor tissue for biomarker assessment....
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109111/ https://www.ncbi.nlm.nih.gov/pubmed/35550553 http://dx.doi.org/10.1136/jitc-2021-004329 |
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author | Gorris, Mark A J van der Woude, Lieke L Kroeze, Leonie I Bol, Kalijn Verrijp, Kiek Amir, Avital L Meek, Jelena Textor, Johannes Figdor, Carl G de Vries, I Jolanda M |
author_facet | Gorris, Mark A J van der Woude, Lieke L Kroeze, Leonie I Bol, Kalijn Verrijp, Kiek Amir, Avital L Meek, Jelena Textor, Johannes Figdor, Carl G de Vries, I Jolanda M |
author_sort | Gorris, Mark A J |
collection | PubMed |
description | BACKGROUND: Immune checkpoint inhibitors (ICI) can lead to long-term responses in patients with metastatic melanoma. Still many patients with melanoma are intrinsically resistant or acquire secondary resistance. Previous studies have used primary or metastatic tumor tissue for biomarker assessment. Especially in melanoma, metastatic lesions are often present at different anatomical sites such as skin, lymph nodes, and visceral organs. The anatomical site may directly affect the tumor microenvironment (TME). To evaluate the impact of tumor evolution on the TME and on ICI treatment outcome, we directly compared paired primary and metastatic melanoma lesions for tumor mutational burden (TMB), HLA-ABC status, and tumor infiltrating lymphocytes (TILs) of patients that received ipilimumab. METHODS: TMB was analyzed by sequencing primary and metastatic melanoma lesions using the TruSight Oncology 500 assay. Tumor tissues were subjected to multiplex immunohistochemistry to assess HLA-ABC status and for the detection of TIL subsets (B cells, cytotoxic T cells, helper T cells, and regulatory T cells), by using a machine-learning algorithm. RESULTS: While we observed a very good agreement between TMB of matched primary and metastatic melanoma lesions (intraclass coefficient=0.921), such association was absent for HLA-ABC status, TIL density, and subsets thereof. Interestingly, analyses of different metastatic melanoma lesions within a single patient revealed that TIL density and composition agreed remarkably well, rejecting the hypothesis that the TME of different anatomical sites affects TIL infiltration. Similarly, the HLA-ABC status between different metastatic lesions within patients was also comparable. Furthermore, high TMB, of either primary or metastatic melanoma tissue, directly correlated with response to ipilimumab, whereas lymphocyte density or composition did not. Loss of HLA-ABC in the metastatic lesion correlated to a shorter progression-free survival on ipilimumab. CONCLUSIONS: We confirm the link between TMB and HLA-ABC status and the response to ipilimumab-based immunotherapy in melanoma, but no correlation was found for TIL density, neither in primary nor metastatic lesions. Our finding that TMB between paired primary and metastatic melanoma lesions is highly stable, demonstrates its independency of the time point and location of acquisition. TIL and HLA-ABC status in metastatic lesions of different anatomical sites are highly similar within an individual patient. |
format | Online Article Text |
id | pubmed-9109111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-91091112022-05-27 Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome Gorris, Mark A J van der Woude, Lieke L Kroeze, Leonie I Bol, Kalijn Verrijp, Kiek Amir, Avital L Meek, Jelena Textor, Johannes Figdor, Carl G de Vries, I Jolanda M J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: Immune checkpoint inhibitors (ICI) can lead to long-term responses in patients with metastatic melanoma. Still many patients with melanoma are intrinsically resistant or acquire secondary resistance. Previous studies have used primary or metastatic tumor tissue for biomarker assessment. Especially in melanoma, metastatic lesions are often present at different anatomical sites such as skin, lymph nodes, and visceral organs. The anatomical site may directly affect the tumor microenvironment (TME). To evaluate the impact of tumor evolution on the TME and on ICI treatment outcome, we directly compared paired primary and metastatic melanoma lesions for tumor mutational burden (TMB), HLA-ABC status, and tumor infiltrating lymphocytes (TILs) of patients that received ipilimumab. METHODS: TMB was analyzed by sequencing primary and metastatic melanoma lesions using the TruSight Oncology 500 assay. Tumor tissues were subjected to multiplex immunohistochemistry to assess HLA-ABC status and for the detection of TIL subsets (B cells, cytotoxic T cells, helper T cells, and regulatory T cells), by using a machine-learning algorithm. RESULTS: While we observed a very good agreement between TMB of matched primary and metastatic melanoma lesions (intraclass coefficient=0.921), such association was absent for HLA-ABC status, TIL density, and subsets thereof. Interestingly, analyses of different metastatic melanoma lesions within a single patient revealed that TIL density and composition agreed remarkably well, rejecting the hypothesis that the TME of different anatomical sites affects TIL infiltration. Similarly, the HLA-ABC status between different metastatic lesions within patients was also comparable. Furthermore, high TMB, of either primary or metastatic melanoma tissue, directly correlated with response to ipilimumab, whereas lymphocyte density or composition did not. Loss of HLA-ABC in the metastatic lesion correlated to a shorter progression-free survival on ipilimumab. CONCLUSIONS: We confirm the link between TMB and HLA-ABC status and the response to ipilimumab-based immunotherapy in melanoma, but no correlation was found for TIL density, neither in primary nor metastatic lesions. Our finding that TMB between paired primary and metastatic melanoma lesions is highly stable, demonstrates its independency of the time point and location of acquisition. TIL and HLA-ABC status in metastatic lesions of different anatomical sites are highly similar within an individual patient. BMJ Publishing Group 2022-05-11 /pmc/articles/PMC9109111/ /pubmed/35550553 http://dx.doi.org/10.1136/jitc-2021-004329 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Immunotherapy Biomarkers Gorris, Mark A J van der Woude, Lieke L Kroeze, Leonie I Bol, Kalijn Verrijp, Kiek Amir, Avital L Meek, Jelena Textor, Johannes Figdor, Carl G de Vries, I Jolanda M Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title | Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title_full | Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title_fullStr | Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title_full_unstemmed | Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title_short | Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome |
title_sort | paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and hla-abc expression whereas tumor mutational load is similar and correlates with clinical outcome |
topic | Immunotherapy Biomarkers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109111/ https://www.ncbi.nlm.nih.gov/pubmed/35550553 http://dx.doi.org/10.1136/jitc-2021-004329 |
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