Cancer immunotherapy via synergistic co-activation of myeloid cells [RNA-seq]
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 ß-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 IFN? 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. Overall design: Comparative gene expression from RNAseq conducted on bulk orthotopic tumors (PDA.7940B mouse tumor cells) untreated or 10 days post-treatment with beta-glucan, anti-CD40 or beta-glucan and anti-CD40