Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer

Philip B. Emmerich; Tonela Qyli; Katherine A. Johnson; Somak Chaudhuri; Kristen M. Clark; Nathaniel B. Verhagen; Mitchell G. Depke; Linda Clipson; Cheri A. Pasch; Athanasios Papadas; Mark E. Burkard; Kari B. Wisinski; Stephanie M. McGregor; Fotis Asimakopoulos; Dustin A. Deming

doi:10.3390/cancers17091435

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Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer

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Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer

Philip B. Emmerich, Tonela Qyli, Katherine A. Johnson, Somak Chaudhuri, Kristen M. Clark, Nathaniel B. Verhagen, Mitchell G. Depke, Linda Clipson, Cheri A. Pasch, Athanasios Papadas, …

Cancers, Vol.17(9), 1435

04/25/2025

DOI: 10.3390/cancers17091435

PMCID: PMC12070914

PMID: 40361362

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Abstract

Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict the exclusion of CD8+ tumor-infiltrating lymphocytes (TILs) in some settings and, thus, is evaluated in breast cancer here. Methods: A total of 230 breast cancers were analyzed for VCAN accumulation, VCAN proteolysis, and CD8+ TILs. CD8+ TILs were categorized based on their localization in the tumor epithelial or stromal compartments. Results: VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%; p < 0.001). MCF7 cells treated with estrogen upregulate VCAN without an enhanced expression of ADAMTS-proteases. VCAN-undetectable tumors demonstrate greater CD8+ TILs compared to VCAN-detectable tumors (p = 0.012). CD8+ T cells within TNBC tumors with high VCAN proteolysis infiltrated the epithelial compartment more often than in tumors with low VCAN proteolysis (91% vs. 42% respectively; p = 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes. Conclusions: VCAN accumulation correlates with the exclusion of CD8+ TILs across subtypes of breast cancer, warranting further validation of VCAN accumulation and proteolysis as predictive biomarkers for breast cancer immunotherapy.

breast cancer

versican

CD8(+) TILs

versikine

estrogen receptor

Details

Title: Subtitle: Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer
Creators: Philip B. Emmerich
Tonela Qyli
Katherine A. Johnson
Somak Chaudhuri
Kristen M. Clark
Nathaniel B. Verhagen
Mitchell G. Depke
Linda Clipson
Cheri A. Pasch
Athanasios Papadas
Mark E. Burkard
Kari B. Wisinski
Stephanie M. McGregor
Fotis Asimakopoulos
Dustin A. Deming
Resource Type: Journal article
Publication Details: Cancers, Vol.17(9), 1435
DOI: 10.3390/cancers17091435
PMID: 40361362
PMCID: PMC12070914
NLM abbreviation: Cancers (Basel)
ISSN: 2072-6694
eISSN: 2072-6694
Publisher: MDPI
Grant note: Funk Out CancerUniversity of Wisconsin Carbone Cancer Center: P30 CA014520 NIH/NCI: R37 CA226526, R01 CA272855
This project was supported by Funk Out Cancer, the University of Wisconsin Carbone Cancer Center (P30 CA014520), and NIH/NCI R01 CA252937. Additionally, the Deming lab is funded by NIH/NCI R37 CA226526 and R01 CA272855.
Language: English
Date published: 04/25/2025
Academic Unit: Internal Medicine
Record Identifier: 9984821345202771

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