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The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma./
作者:	Tung, Navpreet.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	94 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Contained By:	Dissertations Abstracts International81-05B.
標題:	Immunology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=22620117
ISBN:	9781088396667

The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma.
Tung, Navpreet.

The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 94 p.

Source: Dissertations Abstracts International, Volume: 81-05, Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2019.

This item must not be sold to any third party vendors.

Lung cancer is the leading cause of cancer-related deaths worldwide. The preferential retention of T cells to the peritumoral stroma observed in the majority of lung cancer patients has been shown to limit anti-tumor T cell function and the success of T cell-based immunotherapies; therefore, it is crucial to understand the mechanisms regulating T cell exclusion. Our group has previously reported that matrix fibers in the stroma of human lung tumors form a dense physical barrier around tumor islets that restricts T cell contact with tumor cells. Cancer-associated fibroblasts (CAFs) are abundant and the main producers of extracellular matrix proteins within the tumor microenvironment (TME). This led us to hypothesize that CAFs play a key role in regulating T cell distribution at the tumor site and that targeting CAFs may enhance T cell infiltration into the tumor mass. We showed that our lung adenocarcinoma model is associated with progressive T cell exclusion during tumor progression that directly correlated with an activated stromal cell phenotype based on increased expression of -smooth muscle actin. However, local delivery of the viral mimetic, polyI:C, induced significant T cell infiltration into tumor islets. We performed mRNA-sequencing of PDGFRα+ CAFs sorted from late stage tumors and polyI:C-treated tumors leading us to identify candidate genes associated with T cell exclusion, including cytokines, adhesion molecules, and extracellular matrix molecules. Cross-referencing our murine candidate genes with single-cell RNA sequencing data from human lung tumors further established a candidate list of CAF-specific genes that may be involved in mediating T cell exclusion. We subsequently utilized CRISPR/Cas9 lentiviral vectors targeting our CAF-specific gene candidates yielding different CAF lines deficient in each gene of interest. To test these candidates for their effect on T cell exclusion, we developed a novel 3-dimensional spheroid system that physiologically resembled the lung TME consisting of CRISPR CAF lines, lung tumor cells and CD8+ T cells and quantified tumor lysis as a surrogate for infiltration. This "loss-of-function" screen identified NADPH oxidase 4 (nox4) as the top hit. In the absence of NOX4, T cells infiltrated the tumor islets more efficiently proliferated more and produced more type II interferon. Ongoing and future work aims to target NOX4 in combination with checkpoint blockade in our mouse model to observe if we can enhance T cell infiltration and anti-tumor immunity.

ISBN: 9781088396667Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Lung cancer

The Contribution of Cancer-Associated Fibroblasts to T Cell Infiltration in Lung Adenocarcinoma.
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