Spatially Resolved Metabolomics Reveals Tumor-Immune Cell Interactions

Tumor immunometabolism, in other words the intricate interplay of metabolites within a tumor’s microenvironment, is a key determinant of immune cell function and the effectiveness of immune checkpoint blockade therapies. Understanding these metabolic alterations during the antitumor immune response can be challenging. However, a recent study conducted by scientists at Qilu University of Technology and Shandong University of Traditional Chinese Medicine, both in Jinan, China, reports the development of a novel approach to this critical aspect of cancer research (1).

Lymphocytes such as T-cells | Image Credit: © Artur - stock.adobe.com

In their experiment, the findings of which were published in the journal Analytical Chemistry, the researchers created a 3D tumor-immune cell coculture spheroid model. This innovative model was designed to mimic the interactions between immune cells and tumor cells, with the aim of investigating the metabolic changes that occur during the immune response.

More broadly, the study sought to address the challenge of characterizing tumor immunometabolism and its spatiotemporal changes during immune responses within the complex tumor microenvironment. The authors employed mass spectrometry (MS) imaging-based spatially resolved metabolomics to visualize these alterations, and additionally simulated the inhibition and reactivation of T cells to monitor the effects of the immune response.

In the experiment, breast tumor spheroids were cocultured with Jurkat T cells—from an immortalized T lymphocyte cell line originally obtained from the peripheral blood of a boy with T cell leukemia—which mimicked the inhibition of T cells. Subsequent reactivation of T cells was monitored through the reduction of cancer programmed death-ligand 1 (PD-L1) expressions by berberine. Berberine is a plant-derived compound known for its potential in modulating various cellular processes, including metabolism and immunity. By tracking these changes, the researchers could simultaneously screen and image the metabolites that were altered during the T cell-mediated antitumor immune response.

In cancer, T cells are instrumental in the immune response against malignant cells. Tumor-infiltrating lymphocytes, a subset of T cells, can recognize cancer-specific antigens presented on the surface of cancer cells. These activated T cells, known as cytotoxic T cells, target and destroy cancer cells by releasing cytotoxic molecules or inducing apoptosis. A balance is important between the immune response and immune suppression.

One significant discovery made during this investigation was the substantial reprogramming of glutamine transport and catabolism during the antitumor immune response. These changes were observed at both the metabolite and enzyme levels. This reprogramming was linked to the essential roles that glutamine plays in energy metabolism and the creation of new biomass, crucial processes in cellular growth and proliferation.

The innovative combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid model offered a unique perspective on the metabolic interactions between tumor and immune cells. This approach has the potential to provide valuable insights into the role of immunometabolic alterations in tumor immunotherapy.

The spatially resolved metabolomics method used in this study allowed researchers to visualize and analyze metabolite changes in specific regions of the tumor spheroids. This level of detail is critical for understanding how different metabolic processes are distributed within the tumor microenvironment. The findings may pave the way for future research into targeted therapies that manipulate tumor immunometabolism to enhance the effectiveness of cancer treatments.

This article was written with the help of artificial intelligence and has been edited to ensure accuracy and clarity. You can read more about our policy for using AI here.

Reference

(1) Chen, P.; Han, Y.; Wang, L.; et al. Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response. Anal. Chem. 2023, 95 (41), 15153–15161. DOI: 10.1021/acs.analchem.2c05734