2023 World Conference on Lung Cancer (Posters)-P2.15. Priming SCLC Vasculature to Facilitate NK Cell Attack

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Researchers at the Dana-Farber Cancer Institute and Politecnico di Torino have developed a novel method for studying small cell lung carcinoma (SCLC) and neuroendocrine tumors. The researchers aimed to understand the immune response to SCLC and identify potential therapeutic targets. They found that non-neuroendocrine SCLC showed increased innate immune signaling and upregulation of antigen presentation, while neuroendocrine SCLC downregulated major histocompatibility complex class I (MHC-I) expression. <br /><br />To investigate the influence of the vascular barrier on immune cell infiltration, the team developed a three-dimensional microphysiological system (MPS) of the SCLC tumor microenvironment (TIME) in which they perfused NK cells and monocytes through vascularized tumor spheroids. They also used dynamic single-cell RNA sequencing (scRNAseq) to analyze the effect of cGAS-STING agonism on the vascular barrier. <br /><br />The researchers characterized the chemoattractive features of different SCLC cell lines and patient samples using RNA sequencing and cytokine/chemokine assays. They found that neuroendocrine SCLC subpopulations had an inert transcriptional and secretory profile, while MHC-I high SCLC displayed an immunologically active phenotype. Immunofluorescence analysis revealed an immune-desert phenotype in MHC-I low SCLC, but increased NK and T cell infiltration in MHC-I high SCLC at the tumor-stroma interface. <br /><br />Through their MPS model, the team confirmed vascular activation and the production of chemoattractive chemokines and adhesion molecules that promote NK cell extravasation. They also validated the physiological relevance of their ex vivo model by correlating vascular phenotypes to patient-derived SCLC TIME scRNAseq datasets. <br /><br />This study provides insights into the immunological heterogeneity of SCLC and the potential for NK cell-mediated control of MHC-I low SCLC. The researchers developed a well-controlled and adaptable MPS model that can be used for biomarker and therapeutic development for SCLC and neuroendocrine tumors. The model allows for the study of immune infiltration and killing in the tumor microenvironment and the identification of therapeutic vulnerabilities.

Asset Subtitle

Navin Mahadevan

Meta Tag

Speaker Navin Mahadevan

Topic SCLC & Neuroendocrine Tumors: Preclinical

Keywords

small cell lung carcinoma

neuroendocrine tumors

immune response

antigen presentation

vascular barrier

immune cell infiltration

chemoattractive features

RNA sequencing

immunofluorescence analysis

therapeutic vulnerabilities