2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.04: REST represses neuroendocrine transcriptional programs and enables antitumor immunity in SCLC

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