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

TitleT cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control.
Publication TypeJournal Article
Year of Publication2023
AuthorsSteele MM, Jaiswal A, Delclaux I, Dryg ID, Murugan D, Femel J, Son S, Bois Hdu, Hill C, Leachman SA, Chang YH, Coussens LM, Anandasabapathy N, Lund AW
JournalNat Immunol
Date Published2023 Apr
KeywordsCD8-Positive T-Lymphocytes, Humans, Immunotherapy, Lymphatic Vessels, Neoplasms, Receptors, CXCR4

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.

Alternate JournalNat Immunol
PubMed ID36849745
PubMed Central ID5004967
Grant ListR01 AR080436 / AR / NIAMS NIH HHS / United States
R56 AR078686 / AR / NIAMS NIH HHS / United States