T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

Maria M. Steele, Abhinav Jaiswal, Ines Delclaux, Ian D. Dryg, Dhaarini Murugan, Julia Femel, Sunny Son, Haley du Bois, Cameron Hill, Sancy A. Leachman, Young H. Chang, Lisa M. Coussens, Niroshana Anandasabapathy, Amanda Lund

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8+ T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8+ T cells, therefore, exit the tumor, which limits the pool of CD8+ T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.

Original languageEnglish (US)
JournalNature Immunology
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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