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Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer
BACKGROUND: Tonsillar cancer is caused by high-risk human papillomavirus (HPV), tobacco smoking, and alcohol abuse. Aspects of the patient’s immune response to this disease have arisen as prognostic factors and treatment targets, reflecting differences in the type and protein expression profile of i...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691541/ https://www.ncbi.nlm.nih.gov/pubmed/38044986 http://dx.doi.org/10.3389/fonc.2023.1253418 |
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author | Altunbulakli, Can Jimenez, David G. Askmyr, David Sobti, Aastha Swoboda, Sabine Greiff, Lennart Lindstedt, Malin |
author_facet | Altunbulakli, Can Jimenez, David G. Askmyr, David Sobti, Aastha Swoboda, Sabine Greiff, Lennart Lindstedt, Malin |
author_sort | Altunbulakli, Can |
collection | PubMed |
description | BACKGROUND: Tonsillar cancer is caused by high-risk human papillomavirus (HPV), tobacco smoking, and alcohol abuse. Aspects of the patient’s immune response to this disease have arisen as prognostic factors and treatment targets, reflecting differences in the type and protein expression profile of immune cells. Because tonsillar cancers are heterogenous lesions such data need to be spatially resolved. METHODS: In this study, we aim to explore inter-patient and intra-tumoral sources of variation in tonsillar cancer using immunofluorescence and targeted spatial proteomics to interrogate a cohort of 105 patients. Furthermore, we assess prognostic factors and elucidate molecular targets. We have used CD8, CD11c, and Pan-cytokeratin (PanCK) to quantify and locate immune cells driving antigen-specific cellular immunity. Guided by immunofluorescence information, we selected 355 CD8(+), CD11c(+), or PanCK(+) areas inside and outside (i.e., stroma) cancer-cell islets, to quantify 43 immune-related proteins using digital spatial profiling. RESULTS: Quantitative analysis of immunofluorescence in combination with clinical data revealed that the abundance of total CD8(+) cells and CD8(+) cells infiltrating cancer-cell islets, respectively, were associated with higher 5-year disease-free survival and overall survival, independently of HPV-status and clinical stage. Comparison of CD8(+) cells inside and outside cancer-cell islets revealed an upregulation of effector CD8(+) T-cell and immune checkpoint molecules in the former. Among these, the expression of PD-L1 by CD8(+) T-cells was associated with lower all-cause mortality in a univariate proportional hazards model. Similarly, a comparison of tumor boundary and stroma CD11c(+) cells showed upregulation of both co-stimulatory and immune checkpoint molecules with proximity to tumor cell islets. CONCLUSION: Our findings highlight the relevance of analyzing aspects of tumor micro-architecture in the search of prognostic markers and molecular targets for tonsillar cancer. The abundance of intra-tumoral CD8(+) T-cells can be considered a positive predictive marker for tonsillar cancer, while the significance of PD-L1 expression by intra-tumoral CD8(+) T-cells warrants further evaluation. Location-based differences in CD8(+) and CD11c(+) cells suggest an immune cell-altering effect on the tumor microenvironment, and grant new insight into which cells that can be targeted by novel therapeutic agents. |
format | Online Article Text |
id | pubmed-10691541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106915412023-12-02 Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer Altunbulakli, Can Jimenez, David G. Askmyr, David Sobti, Aastha Swoboda, Sabine Greiff, Lennart Lindstedt, Malin Front Oncol Oncology BACKGROUND: Tonsillar cancer is caused by high-risk human papillomavirus (HPV), tobacco smoking, and alcohol abuse. Aspects of the patient’s immune response to this disease have arisen as prognostic factors and treatment targets, reflecting differences in the type and protein expression profile of immune cells. Because tonsillar cancers are heterogenous lesions such data need to be spatially resolved. METHODS: In this study, we aim to explore inter-patient and intra-tumoral sources of variation in tonsillar cancer using immunofluorescence and targeted spatial proteomics to interrogate a cohort of 105 patients. Furthermore, we assess prognostic factors and elucidate molecular targets. We have used CD8, CD11c, and Pan-cytokeratin (PanCK) to quantify and locate immune cells driving antigen-specific cellular immunity. Guided by immunofluorescence information, we selected 355 CD8(+), CD11c(+), or PanCK(+) areas inside and outside (i.e., stroma) cancer-cell islets, to quantify 43 immune-related proteins using digital spatial profiling. RESULTS: Quantitative analysis of immunofluorescence in combination with clinical data revealed that the abundance of total CD8(+) cells and CD8(+) cells infiltrating cancer-cell islets, respectively, were associated with higher 5-year disease-free survival and overall survival, independently of HPV-status and clinical stage. Comparison of CD8(+) cells inside and outside cancer-cell islets revealed an upregulation of effector CD8(+) T-cell and immune checkpoint molecules in the former. Among these, the expression of PD-L1 by CD8(+) T-cells was associated with lower all-cause mortality in a univariate proportional hazards model. Similarly, a comparison of tumor boundary and stroma CD11c(+) cells showed upregulation of both co-stimulatory and immune checkpoint molecules with proximity to tumor cell islets. CONCLUSION: Our findings highlight the relevance of analyzing aspects of tumor micro-architecture in the search of prognostic markers and molecular targets for tonsillar cancer. The abundance of intra-tumoral CD8(+) T-cells can be considered a positive predictive marker for tonsillar cancer, while the significance of PD-L1 expression by intra-tumoral CD8(+) T-cells warrants further evaluation. Location-based differences in CD8(+) and CD11c(+) cells suggest an immune cell-altering effect on the tumor microenvironment, and grant new insight into which cells that can be targeted by novel therapeutic agents. Frontiers Media S.A. 2023-11-17 /pmc/articles/PMC10691541/ /pubmed/38044986 http://dx.doi.org/10.3389/fonc.2023.1253418 Text en Copyright © 2023 Altunbulakli, Jimenez, Askmyr, Sobti, Swoboda, Greiff and Lindstedt 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 | Oncology Altunbulakli, Can Jimenez, David G. Askmyr, David Sobti, Aastha Swoboda, Sabine Greiff, Lennart Lindstedt, Malin Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title | Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title_full | Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title_fullStr | Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title_full_unstemmed | Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title_short | Targeted spatial proteomic analysis of CD8(+) T- and myeloid cells in tonsillar cancer |
title_sort | targeted spatial proteomic analysis of cd8(+) t- and myeloid cells in tonsillar cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691541/ https://www.ncbi.nlm.nih.gov/pubmed/38044986 http://dx.doi.org/10.3389/fonc.2023.1253418 |
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