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Cited by 95Cancer Immunotherapy and BiomarkersLymphatic System and DiseasesT-cell and B-cell Immunology

Lymphatic PD-L1 expression restricts tumor-specific CD8+ T-cell responses

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Cousin, Nikola, Cap, Stefan, Dihr, Manuel, Tacconi, Carlotta, Detmar, Michael, Dieterich, Lothar C.·2021·Cancer Research
DOI 10.1158/0008-5472.can-21-0633PMC PMC9398148

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Abstract

ABSTRACT Lymph node (LN)-resident lymphatic endothelial cells (LECs) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T cell inhibitory molecules, including PD-L1. Tumor-associated LECs also upregulate PD-L1 but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. We generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in a consistent expansion of tumor-specific CD8 + T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased the efficacy of adoptive T cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 primarily acted via apoptosis induction in tumor-specific CD8 + central memory T cells. Our findings demonstrate that LECs restrain tumor-specific immunity via PD-L1 and may explain why some cancer patients without PD-L1 expression in the tumor microenvironment still respond to PD-L1 / PD-1 targeting immunotherapy.

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  • LECs can directly present antigens on MHC class I to CD8 T cells.

    “Last, several studies have indicated that LECs themselves can directly present antigens on major histocompatibility complex class I to CD8 T cells (128–130).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [128]

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Cited by

Sorted by citations

Authors
Cousin, N., Cap, S., Dihr, M., Tacconi, C., Detmar, M., & Dieterich, L. C.
Affiliations
ETH Zurich (CH)
Corresponding author
  • Detmar, Michael
  • Dieterich, Lothar C.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2021-06-07
Volume
81
Issue
15
Pages
4133-4144
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-21-0633
PMC
PMC9398148
OpenAlex
W3170739112
Cited by
95
References
2
Citations by year
2026: 20 · 2025: 18 · 2024: 21 · 2023: 15 · 2022: 18 · 2021: 3
FWCI
5.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Research (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by-nc-nd)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • ETH Zürich Research Collection
Funders
  • Swiss National Science Foundation (310030_166490, 310030B_185392)
  • Vontobel Foundation and Krebsliga Zurich
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
PD-L1, lymphatic endothelial cells, CD8+ T cells, tumor-specific T cell responses, tumor-draining lymph nodes, central memory T cells, T cell apoptosis, tumor immunosuppression, adoptive T cell therapy, melanoma, colorectal cancer, PD-1/PD-L1 blockade
MeSH terms
Animals, Humans, T-Lymphocytes, Transfection, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice, B7-H1 Antigen

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