Tenascin-C immobilizes infiltrating T lymphocytes through CXCL12 promoting breast cancer progression.
CD8 tumor infiltrating lymphocytes
CXCL12
Tumor immune microenvironment
extracellular matrix
tenascin-C
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
revised:
12
04
2021
received:
11
08
2020
accepted:
12
04
2021
pubmed:
15
5
2021
medline:
26
10
2021
entrez:
14
5
2021
Statut:
ppublish
Résumé
Immune checkpoint therapy, where CD8 tumor infiltrating T lymphocytes (TIL) are reactivated, is a promising anti-cancer treatment approach, yet with low response rates. The extracellular matrix, in particular tenascin-C, may generate barriers for TIL. To investigate this possibility, we used a MMTV-NeuNT and syngeneic mammary gland grafting model derived thereof with engineered tenascin-C levels and observed accumulation of CD8 TIL in tenascin-C-rich stroma. Inhibition studies revealed that tenascin-C induced CXCL12 through TLR4. By binding CXCL12, tenascin-C retained CD8 TIL in the stroma. Blockade of CXCR4, the receptor of CXCL12, enhanced macrophage and CD8 TIL infiltration and reduced tumor growth and subsequent metastasis. Retention of CD8 TIL by tenascin-C/CXCL12 was also observed in human breast cancer by tissue staining. Moreover, whereas high CD8 TIL numbers correlated with longer metastasis-free survival, this was not the case when also tenascin-C and CXCL12 levels were high. Altogether, these results may be useful for improving tumor immunity as diagnostic tool and to formulate a future "TIL-matrix-release-and-reactivate" strategy.
Identifiants
pubmed: 33988305
doi: 10.15252/emmm.202013270
pmc: PMC8185552
doi:
Substances chimiques
CXCL12 protein, human
0
Chemokine CXCL12
0
Tenascin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13270Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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