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J Immunol. 2017 Sep 1;199(5):1933-1941. doi: 10.4049/jimmunol.1700529. Epub 2017 Jul 28.

Versican-Derived Matrikines Regulate Batf3-Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer.

Author information

1
Division of Hematology and Medical Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705.
2
University of Wisconsin Carbone Cancer Center, Madison, WI 53792.
3
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705.
4
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705; and.
5
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705.
6
Division of Hematology and Medical Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705; fasimako@medicine.wisc.edu ddeming@medicine.wisc.edu.

Abstract

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+CD11chiMHCIIhi 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.

PMID:
28754680
PMCID:
PMC5568487
DOI:
10.4049/jimmunol.1700529
[Indexed for MEDLINE]
Free PMC Article

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