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862 Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy
  1. Justin Kenkel1,
  2. Po Ho1,
  3. Sameera Kongara2,
  4. Karla Henning1,
  5. Cindy Kreder1,
  6. Jess Nolin1,
  7. Steven Chapin1,
  8. Marcin Kowanetz1,
  9. Michael Alonso1,
  10. Shelley Ackerman1,
  11. Edgar Engleman2 and
  12. David Dornan1
  1. 1Bolt Biotherapeutics, Redwood City, CA, USA
  2. 2Stanford University, Palo Alto, CA, USA


Background Tumor-associated macrophages (TAMs) are an abundant immune cell population in most cancers that support tumor progression through their immunosuppressive effects. We discovered that TAMs express the pattern recognition receptor Dectin-2 (Clec4n/CLEC6A), an activating C-type lectin receptor (CLR) that binds to high-mannose glycans on fungi and other microbes and induces protective immune responses against infectious disease. Dectin-2 is selectively expressed by myeloid cells, and upon ligation mediates enhanced phagocytosis, antigen processing and presentation, and proinflammatory cytokine production. Given these properties, we evaluated the therapeutic potential of targeting Dectin-2 using naturally derived ligands. We also generated human Dectin-2-targeted agonistic antibodies capable of robustly activating immunosuppressive ”M2” or TAM-like macrophages.

Methods Dectin-2 expression was assessed by flow cytometry, immunohistochemistry, and using public databases. Mouse and human monocytes were differentiated into macrophages using recombinant cytokines or tumor-conditioned media, and stimulation was measured following overnight incubation with Dectin-2 ligands or antibodies. Mouse tumor cell lines were implanted into syngeneic hosts and mice were treated with mannan derived from S. cerevisiae via IT or IV administration.

Results Dectin-2 gene expression is minimal in normal human tissues but elevated across many tumor types, including breast, colon, lung, and kidney cancers. Dectin-2 is strongly expressed by macrophages differentiated in vitro and on primary TAMs. The fungal Dectin-2 ligand mannan stimulated proinflammatory cytokine production (e.g. TNFalpha) and costimulatory molecule expression (e.g. CD86) by macrophages in a Dectin-2-dependent manner. Treatment of tumor-bearing mice with mannan mediated tumor regression in multiple syngeneic tumor models, with high rates of tumor clearance in the MB49 bladder cancer model. These effects were Dectin-2 dependent, as efficacy was not observed when a Dectin-2-blocking antibody was co-administered or in knockout mice lacking Dectin-2 signaling components. Furthermore, depletion of either macrophages or T cells impaired efficacy, suggesting that Dectin-2-stimulated TAMs augment anti-tumor T cell responses. Based on these data, we developed novel Dectin-2 targeted agonist antibodies capable of activating human ”M2” or TAM-like macrophages in vitro to produce an array of proinflammatory cytokines and chemokines akin to tumor-destructive ”M1” macrophages.

Conclusions The data presented demonstrate the therapeutic potential of targeting Dectin-2 using natural ligands or agonistic antibodies as a novel pan-cancer approach for myeloid cell-directed tumor immunotherapy.

Ethics Approval All animal studies were performed in accordance with Institutional Animal Care and Use Committee (IACUC)-approved protocols.

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