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

髓系细胞在癌症中介导T细胞免疫逃逸，但其自身具有可塑性并具备抗肿瘤潜能。本研究通过共同靶向激活分子，将髓系细胞群作为癌症治疗的脆弱靶点加以利用。实体肿瘤中的髓系细胞表达多种激活受体，包括模式识别受体CLEC7A（pattern recognition receptor）以及肿瘤坏死因子受体超家族成员CD40（TNF receptor superfamily member CD40）。在免疫检查点抑制剂耐药性胰腺癌的小鼠模型中，通过全身性β-葡聚糖疗法激活CLEC7A，并辅以激动剂抗体靶向CD40，可根除已形成的实体肿瘤并诱导免疫记忆。该抗肿瘤活性依赖于1型经典树突状细胞-T细胞轴（cDC1-T细胞轴），但无需经典T细胞细胞毒性或免疫检查点阻断。相反，靶向CD40可驱动T细胞来源的干扰素γ（IFNγ）信号通路，该通路与CLEC7A激活协同，重塑特定巨噬细胞亚群以促进肿瘤应答。因此，可通过共同激活互补的髓系信号通路，激活有效的癌症免疫监视。总体实验设计：对整块原位肿瘤（PDA.7940B小鼠肿瘤细胞）开展批量RNA测序（RNA-seq），比较未经处理组与分别接受β-葡聚糖、抗CD40抗体，或联合β-葡聚糖与抗CD40抗体治疗10天后的基因表达差异。