Abstract 2883: Dectin-2 agonist antibodies reprogram tumor-associated macrophages to drive anti-tumor immunity

Abstract Tumor-associated macrophages (TAMs), an abundant immune cell population in most cancers, 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 stimulates 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 to reprogram TAMs using natural ligands as well as our novel agonistic antibodies. We show that Dectin-2 agonists can convert TAMs into immunostimulatory cells in vitro and in vivo, and drive robust anti-tumor immunity. Dectin-2 gene expression is minimal in normal human tissues but elevated across many tumor types, including breast, colon, lung, ovarian, and kidney cancers. We found that Dectin-2 is strongly expressed by macrophages differentiated in vitro and on primary TAMs from various solid tumors. Treatment of tumor-bearing mice with mannan, a natural Dectin-2 ligand derived from S. cerevisiae, 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. Depletion of either macrophages or CD8+ T cells impaired efficacy, suggesting that Dectin-2-stimulated TAMs augment anti-tumor CD8+ T cell responses. Based on these data, we developed novel Dectin-2-targeted agonist antibodies capable of activating both in vitro-generated and primary human TAMs to produce an array of proinflammatory cytokines and chemokines akin to tumor-destructive “M1” macrophages. Furthermore, systemically administered Dectin-2 agonist antibodies activated TAMs and mediated anti-tumor effects in immunodeficient mice engrafted with human CD34+ HSCs. The data presented demonstrate the therapeutic potential of Dectin-2 agonist antibodies as a novel pan-cancer approach for myeloid cell-directed tumor immunotherapy. Citation Format: Justin A. Kenkel, Po Y. Ho, Karla A. Henning, Cindy L. Kreder, Jess L. Nolin, Sameera Kongara, Steven J. Chapin, Amreen Husain, Marcin Kowanetz, Edgar G. Engleman, Michael N. Alonso, David Dornan, Shelley E. Ackerman. Dectin-2 agonist antibodies reprogram tumor-associated macrophages to drive anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2883.