Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

Julia Femel, Jamie L. Booth, Tina G. Asnaashari, Sancy A. Leachman, Takahiro Tsujikawa, Kevin P. White, View ORCID ProfileYoung H. Chang, Amanda W. Lund
doi: https://doi.org/10.1101/2021.10.08.463675
Julia Femel
1Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jamie L. Booth
1Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tina G. Asnaashari
2Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239
3OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR, 97239
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sancy A. Leachman
5Department of Dermatology, Oregon Health & Science University, Portland, OR
6Knight Cancer Institute, Oregon Health & Science University, Portland, OR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takahiro Tsujikawa
1Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR
7Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin P. White
5Department of Dermatology, Oregon Health & Science University, Portland, OR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Young H. Chang
2Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239
3OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR, 97239
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Young H. Chang
Amanda W. Lund
1Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR
2Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239
3OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR, 97239
4Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR
5Department of Dermatology, Oregon Health & Science University, Portland, OR
6Knight Cancer Institute, Oregon Health & Science University, Portland, OR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: amanda.lund@nyulangone.org
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

Purpose Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma.

Experimental Design We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas.

Results Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates.

Conclusions We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for tumor cell exit (metastasis) or leukocyte trafficking (immune response).

This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

TRANSLATIONAL RELEVANCE This report describes a quantitative, image-based method to investigate the relationship between the tumor-associated lymphovasculature and immune landscape in treatment naïve, primary human melanoma. The research shows that melanoma-associated blood and lymphatic vessels display context-dependent phenotypes that associate both with the risk of regional progression and immune infiltration. These findings indicate that stromal/vascular heterogeneity may underlie regional differences in immunogenicity and thus present opportunities for future biomarker development and therapeutic intervention.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Financial Support: This work was funded by NIH P30-CA069533, W81XWH-15-1-0348, V2015-024, 403181 (MRA; doi.org/10.48050/pc.gr.44893), and the Cancer Research Institute Clinic and Laboratory Integration Program (CLIP) (AWL). Swedish Research Council Vetenskapsrådet, International postdoc grant (Reg.-Nr: 2016-00215; JF). NIH/NCI U54 CA209988 (YHC). OHSU Knight Cancer Institute’s John D. Gray Endowment (SAL).

  • Conflicts of Interest: The authors declare no relevant financial conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted October 09, 2021.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma
Julia Femel, Jamie L. Booth, Tina G. Asnaashari, Sancy A. Leachman, Takahiro Tsujikawa, Kevin P. White, Young H. Chang, Amanda W. Lund
bioRxiv 2021.10.08.463675; doi: https://doi.org/10.1101/2021.10.08.463675
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma
Julia Femel, Jamie L. Booth, Tina G. Asnaashari, Sancy A. Leachman, Takahiro Tsujikawa, Kevin P. White, Young H. Chang, Amanda W. Lund
bioRxiv 2021.10.08.463675; doi: https://doi.org/10.1101/2021.10.08.463675

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4397)
  • Biochemistry (9632)
  • Bioengineering (7123)
  • Bioinformatics (24940)
  • Biophysics (12671)
  • Cancer Biology (9998)
  • Cell Biology (14405)
  • Clinical Trials (138)
  • Developmental Biology (7989)
  • Ecology (12148)
  • Epidemiology (2067)
  • Evolutionary Biology (16026)
  • Genetics (10953)
  • Genomics (14778)
  • Immunology (9907)
  • Microbiology (23739)
  • Molecular Biology (9508)
  • Neuroscience (51056)
  • Paleontology (370)
  • Pathology (1545)
  • Pharmacology and Toxicology (2694)
  • Physiology (4038)
  • Plant Biology (8696)
  • Scientific Communication and Education (1512)
  • Synthetic Biology (2404)
  • Systems Biology (6459)
  • Zoology (1350)