Journal
JOURNAL OF IMMUNOLOGY
Volume 199, Issue 5, Pages 1933-1941Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700529
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Funding
- American Cancer Society [RSG-15-01-LIB]
- University of Wisconsin Carbone Cancer Center Trillium Fund for Multiple Myeloma Research
- Funk Out Cancer funds
- Bowlin' for Colons funds
- Cathy Wingert Colorectal Cancer Research Fund
- V Foundation Scholar Award
- National Institutes of Health [P30CA014520, T32HL007899]
- University of Wisconsin Cellular and Molecular Pathology graduate training program
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Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8(+) T cell infiltration in colorectal cancer, regardless of mismatch repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). Versikine, a VCAN-derived matrikine, enhanced the generation of CD103(+)CD11c(hi)MHCII(hi) conventional dendritic cells (cDCs) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors toward IRF8- and BATF3-expressing cDCs. Intratumoral BATF3-dependent DCs are critical determinants for T cell antitumor immunity, effector T cell trafficking to the tumor site, and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.
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