Alveolar Type I Cells Can Give Rise to Kras-Induced Lung Adenocarcinoma

Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma

“…A recent study in which a mathematical model that accounts for the effect of MDSC suppression on tumor progression was validated on a cohort of lung cancer patients, further supporting the importance of suppression on tumor progression 116,117 . This body of work, among others 13,118,119 , provides supporting evidence that LUAD heterogeneity may arise in part from multiple alveolar cell state origins, and design strategies for the next generation of therapeutic strategies in LUAD must begin to incorporate multiple cellular origins into their modeling to improve accuracy of testing and development..…”

“…Further investigating this difference in myeloid populations, we utilized a previously published spatial transcriptomic (ST-seq) dataset on an independent cohort of Sftpc + KRAS G12D LUAD, Gramd2 + KRAS G12D LUAD 13 , and controls to determine the frequency of macrophage-rich tertiary lymphoid structure (TLS), which emerge in non-lymphoid tissues under chronic inflammatory conditions, such as cancer 48 and play a crucial role in immune surveillance by facilitating the local activation of immune responses against tumor cells 49 with associated responsiveness to immunotherapies, such as immune checkpoint inhibitors [50][51][52][53] . TLS were calculated using a composite score expression for multiple immune cell types, including B cells: Igha, Ighg1, Ighg3, Ighm, Igkc, Iglc1, Iglc2, Iglc3, Jchain, Cd79a, Fcrl5, Mzb1, Ssr4, Xbp1; T cells: Trbc2, Il7r; for fibroblasts and stroma: Cxcl12, Lum; and for macrophages: C1qa, C7, Cd52, Apoe, Pim2, Derl3, Timd4, Cd163, and Folr2.…”

“…Salmon = endothelial: capillary, gold = endothelial: main, peridot = epithelial: airway, green = epithelial: alveolar, seafoam = immune: innate lymphoid, teal = immune: lymphoid, blue = immune: myeloid, purple = mesenchymal: airway, magenta = mesenchymal: alveolar, and pink = mesenchymal: pleura. g, Spatial transcriptomic profiles of previously generated dataset 13 overlaid with tertiary lymphoid structure (TLS) composite score. Red = high TLS score, blue = low TLS score.…”

“…A Kruskal Wallis test was used to test the significance of the difference of mean macrophage reactivity score overall (p value < 2.2e-16), and a pairwise Wilcoxon test was used to determine significance of differences between individual experimental groups, p value < 2e- 16 ). *p < 0.05, **p < 0.01, ***p < 0.001. d, Violin plot of aggregate myeloid suppression score across all experimental groups based on the previously published ST-seq dataset 13 . Experimental groups are colored as in (c).…”

“…Previous research has demonstrated that mouse models driving expression of oncogenic Kristen RAt Sarcoma viral oncogene homolog (KRAS)-G12D amino acid mutation in Sftpc + AT2 cells give rise to lesions histologically similar to human LUAD [9][10][11] . In addition, recent studies have established that Gramd2 + and Hopx + AT1 cells can also give rise to KRAS G12D -driven LUAD 12,13 . However, how cell of origin influences the immune landscape within the tumor immune microenvironment (TIME) in LUAD is poorly understood.…”