Exploring the translational potential of influencing macrophage polarization in the tumor microenvironment in small cell lung cancer with a Boolean control network model
Szegvári Gábor Adrián
KÁROLY RÁCZ CONSERVATIVE MEDICINE PROGRAM
Dr. Reusz György
SE Elméleti Orvostudományi Központ, Hevesy György előadóterem
2024-06-21 15:00:00
Respiratory diseases
Dr. Lohinai Zoltán
Dr. Fekete János
Dr. Korcsmáros Tamás
Dr. Győrffy Balázs
Dr. Schvarcz Csaba
Dr. Simon Zoltán
Translational research of the tumor microenvironment (TME) is an emerging field of study that has resulted in therapeutic developments in multiple types of cancers recently. Our understanding of the TME of small cell lung cancer (SCLC) is incomplete, severely limiting therapeutic prospects and the application of the newest advances in the field. We aimed to gain new insights about the immune cells in the SCLC TME, with special attention to tumor associated macrophages (TAMs) and their polarization state, to reveal molecular targets for therapeutic intervention.
First, we characterized the cellular environment regulating anti tumor immunity in limited stage neuroendocrine (NE) high and NE low SCLC subsets, including lymph node metastases. Immunohistochemical labeling and cell counting on TMAs (tissue microarrays) showed that overall immune infiltration is low, and that TAMs are the most abundant cell type in the tumor nest TME, exceeding CD3+ T cells. Also, the amount of CD163+ M2 polarized TAMs is significantly higher in NE low (vs. NE high) tumor nests. TAM density shows a strong positive correlation with CD45 and CD3 in primary tumor nests, but not in the stroma. We identified potential molecular targets based on our expression data in NE low and infiltration high tumor subsets.
Next, we propose an in silico approach aimed at understanding the intracellular systems driving polarization and their dependence on extracellular cues. We create and verify a Boolean Control Network model, connecting extracellular signals with the gene transcription to model the early response in macrophages. We observe that inflammatory and regenerative pathways show a difference in architecture. Based on simulations of therapeutic intervention, we conclude that inhibition of single targets is insufficient to change an established polarization in most cases. Inhibition of multiple targets (often with an individually weak effect) is necessary, with STAT6, JAK1 and JAK3 emerging as important targets to push toward M1 and NFAT5 toward M2.
To facilitate the use of large databases we present a novel, open access platform aimed at drug repurposing that we call EZCancerTarget, aggregating data from databases such as PubChem, DrugBank, PubMed, and EMA, complete with biological background information and literature citations for every target from UniProt, String, GeneCards and more. The content of the platform can be expanded or replaced by users to suit their purposes.
