Investigating nanotube-mediated mitochondria transfer and inhibitor effects in cancer-immune cell interactions across 2D and 3D models

Project Summary/Abstracts This supplementary project aims to uncover the mechanisms and implications of mitochondria transfer between immune cells and cancer cells via tunneling nanotubes (TNTs), specifically focusing on the potential of inhibiting these transfers to boost the efficacy of immunotherapies against cancer. Through the development and

application of 2D and 3D models, the study intends to explore how these mitochondrial transfers affect cancer cell behavior across various macrophage phenotypes under different experimental conditions. A central goal of the research is to assess the effectiveness and safety of nanotube inhibitors, thus providing new insights into

their potential to enhance current immune checkpoint therapies by disrupting TNT-mediated interactions between cancer and immune cells. Structured into three aims, the project will first characterize mitochondria trafficking between cancer cells and macrophages via TNTs, focusing on the influence of macrophage phenotypes on cancer cell fate. This aim is

critical for understanding the nanotube-mediated mechanisms that cancer cells may use to evade immune responses, potentially undermining the effectiveness of immune checkpoint inhibitors. The second aim will develop 3D models that more accurately mimic physiological conditions for studying TNT dynamics than

traditional 2D models. This is vital for gaining insights into the unique structural and functional properties of TNTs in 3D environments, especially regarding their interactions with the extracellular matrix (ECM) and its significant impact on TNT formation and functionality. The final aim evaluates the efficacy of various nanotube inhibitors,

including those targeting the exocyst complex, in preventing TNT formation and mitochondrial transfer between cancer cells and macrophages. This includes examining the effects of these inhibitors on macrophage immune responses to cancer cells, with the overarching objective of enhancing anti-cancer immune activities in 3D

models. This project addresses the gap in understanding the role of macrophages in immune responses to cancer cells, particularly focusing on nanotube-mediated mitochondrial transfer and its implications for immune evasion. By exploring these interactions in various 2D and 3D settings, the research aims to uncover novel insights into the

dynamically-changing structural and functional characteristics of TNTs. This understanding is expected to aid in creating targeted therapies that enhance immune checkpoint inhibitor efficacy, contributing to the advancement of cancer immunotherapy strategies.