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Brief description/objective

Lung cancer is the most frequent cause of death in cancer patients in industrialized countries. A particular property of non-small cell lung cancer is the composition of the tumor microenvironment (TME) with a very high proportion of stromal cells. Whereas the stroma of normal tissues represents a natural barrier for tumor cells, the stroma within cancer tissues has coevolved with the neoplastic tissue to support its growth and spread. In particular, fibroblasts can be reprogrammed to secrete growth factors, proteases and extra-cellular matrix components that support tumor progression.
Nevertheless, recent studies reveal that subsets of fibroblasts can play a tumor-suppressive role, providing an explanation as to why global anti-stromal cell therapies have sometimes resulted in exacerbated malignant growth. Hence, it is important to determine the origin of such tumorsuppressive fibroblastic stromal cells (FSC) and to delineate the molecular pathways that govern fibroblast differentiation in the tumor milieu. Moreover, expression of several immune-stimulating
genes that mediate attraction of immune cells and/or foster formation of protective tertiary lymphoid structures, is associated with improved survival of lung cancer patients. However, little is known about the nature of the fibroblastic cells that determine the establishment of such immune-stimulating niches in the lung cancer microenvironment.
The main hypothesis underlying the planned research is that expansion and maturation of a distinct fibroblast subset fosters the development of immune-stimulating microenvironments within the lung tumor, which in turn promotes antitumor immunity. We have designed an interdisciplinary approach to dissect the origin, identity, and function of immune-stimulating fibroblasts in relation to other fibroblast subsets of the lung tumor stroma. The work on the first aim of the research program is built on the assumption that a lineage of tissue-resident fibroblasts exhibits immune-stimulating potential once exposed to the tumor microenvironment. Novel fibroblast subset-specific fate-mapping models will be used to define the differentiation trajectories of immune-stimulating FSC at single-cell resolution during lung cancer development. The goal of the second aim is to establish a causal relationship between the maturation of immune-stimulating fibroblasts in the lung TME and the formation of tumor-associated tertiary lymphoid structures. To this end, cell type-specific ablation of key fibroblast maturation factors and targeted ablation of immune-stimulating fibroblasts in experimental lung tumors will be utilized to
assess the impact of such fibroblasts on antitumor immunity. The goals of the third aim are to identify immune-stimulating FSC in human lung cancer and to develop a data-based model of tumor-induced changes to the lung stroma. To gauge the transcriptional diversity between fibroblast lineages within the tumor stroma, RNA-sequencing (RNA-seq) of small, defined cohorts of fluorescently-marked
fibroblasts will be performed. Single-cell RNA-seq of human lung cancer FSC will be complemented in the fourth aim by single-cell mass cytometry to provide important information for refined subset definition. Finally, we will validate our data-based model of lung fibroblast differentiation using tissue mass cytometry on lung and tumor tissue from patients with adenocarcinoma or squamous cell
carcinoma.
Together, the collaborative approach proposed here will reveal novel insight into the origin, identity, function and relation of immune-stimulating fibroblasts in the context of the lung tumor stroma.
Moreover, we expect that these studies will reveal putative therapeutic targets to bias the composition of the tumor stroma by promoting the differentiation of an immune-stimulating environment.