Spatial Quantification of Cellular Metabolism in the Tumor Immune Microenvironment

Introduction

The success of cancer immunotherapy, especially immune checkpoint inhibition (ICI), demonstrates the ability of the immune system to fight tumors. However, only a fraction of patients benefit from currently available therapies, and we need to find novel approaches to improve clinical responses.

Background

Cellular metabolism has emerged as a key determinant of multiple aspects of immune cell function, especially T cell exhaustion and anti-inflammatory macrophage polarization. However, we currently do not have a good understanding of the metabolic states of human immune cells since no technology has been available to quantify them directly in clinical tumor tissues.

Hypothesis

I hypothesize that tumors create spatially defined metabolic environments, also called metabolic niches, to suppress immune cells and that this mechanism can be targeted to improve cancer immunotherapy.

Objectives

To test this hypothesis, we will:

1. Quantify the metabolic states of immune cells in solid human cancers.
2. Identify metabolic immune cell states that predict response to ICI.
3. Reveal the mechanism of metabolic niche formation in tumor organoids.

Methodology

We will quantify cellular metabolism and phenotype directly in human tumor tissues, using the innovative single-cell metabolic profiling (scMEP) approach I have recently developed. We will combine this with multiplexed ion beam imaging (MIBI), a technology that enables 40-dimensional proteomic imaging.

MIBI imaging will be complemented by:

• Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI).
• Machine learning frameworks for the analysis of these multi-omic datasets.

Conclusion

Taken together, this project will uncover generalizable concepts of how different tumor entities influence the cellular metabolism of immune cells to modulate their function. The potential therapeutic targets that will emerge from this analysis could thus contribute to improved treatment options for various types of human cancer.