Versican-Derived Matrikines Regulate Batf3-Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer. J Immunol 2017 Sep 01;199(5):1933-1941
Date
07/30/2017Pubmed ID
28754680Pubmed Central ID
PMC5568487DOI
10.4049/jimmunol.1700529Scopus ID
2-s2.0-85028024683 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
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.
Author List
Hope C, Emmerich PB, Papadas A, Pagenkopf A, Matkowskyj KA, Van De Hey DR, Payne SN, Clipson L, Callander NS, Hematti P, Miyamoto S, Johnson MG, Deming DA, Asimakopoulos FAuthors
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinDana Van De Hey Physician Assistant in the Neurology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBasic-Leucine Zipper Transcription Factors
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Movement
Cells, Cultured
Colorectal Neoplasms
Dendritic Cells
Extracellular Matrix
Humans
Immunotherapy
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating
Mice
Mice, Inbred C57BL
Proteolysis
Repressor Proteins
Tumor Microenvironment
Versicans
