Revealing the immune tumor microenvironment (iTME) in melanoma by multiplexed imaging

Descripción del proyecto

Desvelar el papel del microentorno del melanoma en la respuesta a la inmunoterapia

Los tumores son combinaciones organizadas en el espacio de diferentes tipos celulares con fenotipos definidos por la coexpresión de múltiples proteínas. El microentorno tumoral inmune desempeña un papel fundamental en las interacciones entre las células inmunitarias y estromales, pues define la progresión y la respuesta al tratamiento. Una plataforma de imagenología multiplexada de haz de iones recientemente desarrollada permite la toma de imágenes simultánea de cuarenta proteínas en secciones tisulares intactas a una resolución subcelular. El proyecto financiado con fondos europeos ImageMelanoma se propone utilizar esa plataforma para investigar el microentorno tumoral inmune en docenas de muestras y definir su función en respuesta a diferentes inmunoterapias. El estudio caracterizará los tumores de melanoma para dilucidar los mecanismos que dirigen la organización del microentorno tumoral inmune, desarrollar nuevas herramientas experimentales para rastrear y codificar miles de células tumorales y emplear algoritmos basados en el aprendizaje automático para el análisis de datos.

Objetivo

Immunotherapies targeting immune regulators are revolutionizing cancer treatment, most prominently in melanoma, but only for a subset of patients. While it is known that the immune tumor microenvironment (iTME) plays a vital role in this process, there is limited understanding on how distinct tumor, immune and stroma cells interact as a system to collectively define progression and response to treatment, and there is no biomarker to predict patient response. Tumors are spatially organized ecosystems that are comprised of distinct cell types, each of which can assume a variety of phenotypes defined by coexpression of multiple proteins. To underscore this complexity, and move beyond single cells to multicellular interactions, it is essential to interrogate cellular expression patterns within their native context in the tissue.

We have recently pioneered MIBI-TOF (Multiplexed Ion Beam Imaging by Time of Flight), a novel platform that enables simultaneous imaging of forty proteins within intact tissue sections at subcellular resolution. We propose to (1) Use MIBI-TOF to chart the iTME in dozens of clinical samples from melanoma patients and delineate its function in response to different immunotherapies. (2) Profile murine melanoma tumors to elucidate genetic and temporal mechanisms that drive iTME organization in vivo. (3) Develop new experimental tools for tracing and barcoding thousands of cells to decouple the effects of tumor genetics and the immune microenvironment on tumor organization and clonal dynamics. (4) Develop machine-learning-based algorithms to analyze this novel data and facilitate accessibility of the scientific community to high-dimensional imaging to study human malignancies.

This proposal applies state-of-the-art imaging technology and computation to unravel design principles of the iTME in melanoma, with a grand goal to reveal basic principles in tumor immunology and improve treatment and diagnostics.