Steele et al. demonstrated that lymphatic vasculature helps to tune the diversity and functional state of the intratumoral CD8+ T cell repertoire and promotes tumor immune evasion. Lymphatic vessel-derived CXCL12 sequestered CD8+ T cells at the tumor periphery and facilitated CXCR4-dependent egress of a broad repertoire of functional CD8+ T cells. High-affinity antigen encounter downregulated CXCR4 and promoted T cell retention. CXCR4 inhibition, CXCR4 deletion in CD8+ T cells, or loss of lymphatic-specific CXCL12 improved T cell retention and enhanced tumor control and ICB efficacy in a preclinical melanoma model.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. Department of Cell, Developmental and Canc
Author Info: (1) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (2) Department of Dermatology, Microbiology and Immunology, Meyer Cancer Center, Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (3) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. (4) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. (5) Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (6) Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (7) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. Applied Bioinformatics Laboratories, NYU Langone Health, New York, NY, USA. (8) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. (9) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. (10) Department of Dermatology, Oregon Health and Science University, Portland, OR, USA. (11) Department of Biomedical Engineering and Computational Biology Program, Oregon Health and Science University, Portland, OR, USA. OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR, USA. (12) Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (13) Department of Dermatology, Microbiology and Immunology, Meyer Cancer Center, Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (14) Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. amanda.lund@nyulangone.org. Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. amanda.lund@nyulangone.org. Department of Pathology, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. amanda.lund@nyulangone.org. Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York University Langone Health, New York, NY, USA. amanda.lund@nyulangone.org.
