实体癌通常是高度异质性的癌症，由多个起源上皮细胞产生。然而，人们对起源细胞如何影响肿瘤微环境的反应知之甚少。肺腺癌 (LUAD) 发生于远端肺泡上皮，主要由 I 型 (AT1) 和 II 型 (AT2) 肺泡上皮细胞组成。先前已报道，Gramd2 AT1 细胞可以产生组织学上定义的 LUAD，其在病理学和转录组学特性上与 Sftpc AT2 细胞产生的 LUAD 不同 1,2 。为了确定起源细胞如何影响肿瘤免疫微环境 (TIME) 景观，我们使用 KRAS G12D 致癌驱动小鼠模型全面表征了 Gramd2 AT1 和 Sftpc AT2 衍生的 LUAD 在 TIME 内的转录组、分子和细胞状态。 Gramd2 AT1 衍生的 LUAD TIME 内的骨髓细胞增加，特别是免疫反应性单核细胞和肿瘤相关巨噬细胞 (TAM)。相比之下，Sftpc AT2 LUAD TIME 富含精氨酸酶-1 骨髓源性抑制细胞 (MDSC) 和 TAM，表达谱表明具有免疫抑制功能。使用流式细胞术对免疫浸润进行验证，原始细胞和主要骨髓细胞群之间的细胞间相互作用分析表明，AT2 细胞中的细胞类型特异性标记物 SFTPD 和 AT1 细胞中的 CAV1 介导与差异免疫抑制的骨髓细胞的独特相互作用。原始小鼠模型的每个细胞内的状态。总而言之，Gramd2 AT1 衍生的 LUAD 具有抗肿瘤、免疫反应性 TIME，而 Sftpc AT2 衍生的 LUAD 的 TIME 具有免疫抑制的特征。这项研究表明，LUAD 细胞起源影响 TIME 景观的组成和抑制状态，并可能对患者对免疫治疗的反应具有重要影响。

Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that Gramd2 + AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from Sftpc + AT2 cells 1,2 . To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of Gramd2 + AT1 and Sftpc + AT2-derived LUAD using KRAS G12D oncogenic driver mouse models. Myeloid cells within the Gramd2 + AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the Sftpc + AT2 LUAD TIME was enriched for Arginase-1 + myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, Gramd2 + AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of Sftpc + AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.