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936 Stromal remodeling regulates dendritic cell abundance in the tumor microenvironment
  1. Athanasios Papadas1,
  2. Gauri Deb1,
  3. Adam Officer1,
  4. Chelsea Hope2,
  5. Philip Emmerich2,
  6. Alexander Cicala1,
  7. Joshua Wiesner1,
  8. Garrett Arauz1,
  9. Adam Pagenkopf2,
  10. Kristina Matkowskyj2,
  11. Dustin Deming2,
  12. Katerina Politi3,
  13. Scott Abrams4,
  14. Olivier Harismendy1 and
  15. Fotis Asimakopoulos1
  1. 1UCSD, La Jolla, CA, USA
  2. 2UW-Madison, Madison, WI, USA
  3. 3Yale, New Haven, CT, USA
  4. 4Roswell Park, Buffalo, NY, USA


Background Stimulatory dendritic cells (SDC), enriched within the Batf3-DC lineage (also known as conventional type 1 DC, cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. This puzzling pattern of T-cell-DC localization has been interpreted as ”tumor-exclusion”, limiting anti-tumor immunity. To understand this paradox, we hypothesized that dynamic matrix remodeling at the invasive margin generates unique activation and cell-fate cues critical for Batf3-DC homeostasis.

Methods We studied immunocompetent tumor models of lung carcinoma, breast carcinoma, melanoma and multiple myeloma. For mechanistic experiments, we generated novel Vcan-targeted models through CRISPR-Cas9 targeting. We delineated DC subsets through multi-parametric flow cytometry and tumor immune contexture through mass cytometry. Batf3-DC cellular models included MutuDC1940 immortalized DC and iCD103 primary cells. TCGA data were mined for human validation.

Results We find that CD8+ T cells massively infiltrate tumor matrices undergoing robust matrix proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. Across 7591 samples from 20 TCGA cancer types, a significant-positive correlation between VCAN substrate expression and Batf3-DC score was observed, suggesting that the VCAN pathway may regulate Batf3-DC across several cancer types. Experimental Vcan depletion in the tumor microenvironment was detrimental for Batf3-DC. Batf3-DC abundance was restored through the VCAN N-terminal fragment (matrikine) versikine, physiologically generated through ADAMTS protease activity in remodeled stroma. In addition to Batf3-DC expansion, versikine resulted in G-MDSC contraction as well as the emergence of an atypical innate lymphoid (NK/ILC1) subset expressing cytotoxicity receptors, low IFNgamma and robust pro-survival GM-CSF. Despite broad intratumoral IRF8 induction (10-100-fold), adoptive transfer of pre-DC into versikine-replete microenvironments did not influence their differentiation choice between Batf3-DC and cDC2. Instead, versikine delivered a distinct Batf3-DC activation signal characterized by non-TLR maturation as well as downregulation of TGFbeta and Wnt signaling. In vivo, versikine promoted Batf3-DC abundance through NK cells but independently of stromal TLR2 or CD44. Versikine sensitized immune-evasive tumors to STING agonist immunotherapy in a Batf3-DC dependent manner and promoted antigen-specific CD8+ responses. Versikine-DC signatures correlated with CD8+ T cell scores in human lung cancers.

Conclusions We demonstrate that dynamic extracellular matrix remodeling controls Batf3-DC abundance in the tumor microenvironment. N-terminal proteolysis of the matrix proteoglycan versican (VCAN), releases a bioactive fragment (matrikine), versikine, that is remarkably necessary and sufficient for Batf3-DC accumulation. Versikine orchestrates a multi-lineage network that regulates Batf3-DC activation and survival at matrix-remodeling interfaces. Therapeutic harnessing of matrix-Batf3-DC cross-talk sensitizes immune-evasive tumors to immunotherapy.

Acknowledgements We acknowledge support by the National Cancer Institute (R01CA252937 and U01CA196406), the American Cancer Society (127508-RSG-15-045-01-LIB), the Leukemia and Lymphoma Society (6551–18), the UW Trillium Myeloma Fund and the Robert J. Shillman Foundation.

Ethics Approval Laboratory animal work was performed under IACUC-approved protocols #M5476 and #S19109 in the University of Wisconsin-Madison and University of California, San Diego respectively.

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