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PP01.04: REST represses neuroendocrine transcripti ...
PP01.04: REST represses neuroendocrine transcriptional programs and enables antitumor immunity in SCLC
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The document outlines research on the role of the transcription factor REST in small-cell lung cancer (SCLC), highlighting its effects on tumor biology and potential therapeutic implications. The study begins by identifying a subset of SCLC patient-derived xenograft (PDX) models with low-neuroendocrine features and elevated REST expression, termed the REST-I subset. Overexpression of REST in murine models is shown to reduce neuroendocrine differentiation, enhance inflammatory responses, and promote histological diversity, with notable changes in gene expression patterns related to inflammation and immune response.<br /><br />REST improves the response of SCLC tumors to PD1 immune checkpoint blockade, with REST overexpression leading to increased infiltration of CD8 T cells and macrophages in the tumor microenvironment. These immune changes are associated with a heightened immune response, including upregulation of MHC-I antigen presentation in cells treated with interferon-gamma.<br /><br />Flow cytometry analysis of REST-overexpressing syngeneic allografts shows significant immune modulation, characterized by increased expression of inflammatory gene signatures and the expansion of a CD8 PD1 Tim3 T cell subset.<br /><br />Experimental results demonstrate that REST overexpression in SCLC can create tumors with mixed neuroendocrine and inflammatory characteristics, making them more susceptible to immune checkpoint therapies. This suggests that targeting REST in SCLC may enhance anti-tumor immunity by shifting tumors towards a more inflamed phenotype, potentially improving responses to therapies like PD1 inhibitors. The study acknowledges contributions from various institutions and funding bodies supporting this research.
Asset Subtitle
Navin Mahadevan
Keywords
REST
small-cell lung cancer
SCLC
tumor biology
immune checkpoint blockade
neuroendocrine differentiation
PD1 inhibitors
immune response
inflammatory gene signatures
tumor microenvironment
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