Project description:The goal of this study was to define the impact of beta-glucan (CLEC7A agonist), anti-CD40 (agonist) and the combination of beta-glucan and anti-CD40 on the intra-tumoral immune landscape of mouse orthotopic pancreatic tumors using single-cell RNA sequencing.
Project description:Myeloid cells coordinate T cell immune evasion in cancer yet are pliable and possess anti-tumor potential. Here, by co-targeting activation molecules we leverage the myeloid compartment as a therapeutic vulnerability in cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor CLEC7A and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, co-activation of CLEC7A, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Anti-tumor activity was dependent on a cDC1 – T cell axis but did not require classical T cell cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-derived IFNγ signaling which converged with CLEC7A activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance can be invoked by co-activation of complementary myeloid signaling pathways.
