Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing and multiplex immunohistochemistry on patient tumors, matched blood and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patients’ T cells and increased markers of CD8⁺ T cell dysfunction in the advanced disease stage. Tumor-infiltrating CD8⁺ T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.

胰腺导管腺癌（PDA）的特点是免疫抑制性肿瘤微环境，使其在很大程度上难以接受免疫治疗。我们采用多模式分析方法来阐明 PDA 中的免疫景观。通过结合 CyTOF、单细胞 RNA 测序和多重免疫组织化学对患者肿瘤、匹配的血液和非恶性样本进行分析，我们发现了免疫抑制细胞相互作用的复杂网络。这些实验揭示了个体患者 T 细胞中免疫检查点受体的异质表达，以及晚期疾病阶段 CD8 ⁺ T 细胞功能障碍的标志物增加。肿瘤浸润 CD8 ⁺ T 细胞中表达耗尽表达谱的细胞比例增加，其中包括免疫检查点TIGIT的上调，我们在蛋白质水平上验证了这一发现。我们的研究结果表明肿瘤的免疫格局发生了深刻的改变，并且随着联合免疫疗法可用于胰腺癌，应考虑患者特异性的免疫变化。