ABSTRACT: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer with extensive biological heterogeneity, such as varying cells of origin from alveolar epithelial cells (AECs) in the distal lung. The predominant types of AECs include surfactant-producing alveolar epithelial type II (AT2) cells and large, delicate alveolar epithelial type I (AT1) cells, which are responsible for facilitating gas exchange. Although AT1 cells have been thought to be terminally differentiated and consequently unable to proliferate, we, and others, have previously reported that Gramd2+ AT1 cells can give rise to a histologically-defined LUAD1,2 on transgenic mouse model. Immunotherapy has shown a major impact on treatment of solid tumors over the past 10 years, particularly on LUAD, where it significantly improves patients’ survival rates3. However, because of the largely unknown immunosuppressive states of LUAD, there is considerable variability in patient response to therapy across LUAD patients, making immunotherapeutic treatment challenging. To determine whether cells of origin for LUAD reprogram differently tumor immune microenvironment (TIME) landscape, we employed single nucleus RNA sequencing (snRNA-Seq) on mouse KRASG12D-overexpressing Gramd2+ AT1 cell and Sftpc+ AT2 cell-derived LUADs to comprehensively characterize transcriptomic, molecular, and cellular aberrations within the TIME. We demonstrate that myeloid cells within the AT1-LUAD TIME manifest a disordered cell composition and disrupted transcriptome: increased cell number of inflammatory monocytes and macrophages but decreased cell number of myeloid-derived suppressor cells (MDSCs) were observed in AT1-LUAD TIME compared with its AT2 counterpart. In addition, a series of bioinformatic analyses, gene set enrichment analysis (GSEA), ingenuity pathway analysis (IPA) and cell-cell communication (CCC) analysis, along with immunostaining confirmed LUAD TIME derived from different cells of origin exhibits altered suppressive gene expression patterns and disparate pro-inflammatory signaling activities. Taken together, AT1-LUAD presents a proinflammatory, immunoreactive TIME, while the TIME of AT2-LUAD is relatively immunosuppressive. This study suggests that LUAD cell of origin is associated with transcriptomic aberrations and immune landscape changes that may inform ongoing translational work to improve patient responses.
