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Gene expression profile of colorectal cancers with microarray

ABSTRACT: We have found that some tumor infiltrating lymphocytes in colorectal cancer (CRC) tumor expressed low intensity of FOXP3 with flow cytometry assays, resulting in the presence of certain amount of tumor infiltrating FOXP3lo cells in subpopulation of CRC tumor tissues. To clarify different gene expression paterns between CRC tumors with high FOXP3lo cell infiltration and without these cell infilrtraion, we performed microarray analyses with total mRNA extracted from whole tumor tissues with high FOXP3lo cell infiltration (n=2) and low FOXP3lo cell infiltration (n=2). Comparison of gene expression profiles revealed that genes involved in immune responses and inflammation were significantly up-regulated in tumor with high FOXP3lo cell infiltration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79038 | GEO | 2016/04/22

SECONDARY ACCESSION(S): PRJNA314767

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Gene expression profile of colorectal cancers with microarray

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