Background:
Immunotherapy use is increasing across cancer types, however, how the nutrient microenvironment affects immune cell activity is not fully understood [1]. We addressed this challenge using a novel framework combining nutrient distributions within a tumor, single cell RNA-seq data, and genome-scale metabolic modeling [2] to understand how immune cell cytotoxic potential varies within tumor microenvironments.
Methods:
We constructed 3D nutrient composition atlases of over 1200 breast cancer tumors using the SimBioSys TumorScope software. We then constructed a genome-scale metabolic model of tumor infiltrating T-cells based on single cell RNA-sequencing data from over 5000 single T-cells from breast cancer patients. We simulated this T-cell metabolic model across the range of nutrient compositions present in our tumor atlases to understand how nutrient availability affects the cytotoxic potential of T-cells.
Results:
Our results demonstrated that the local nutrient composition has a dramatic impact on T cell functionality, with fundamental cellular behaviors being significantly impaired by a reduction in key nutrients such as glucose and oxygen. Additionally, the degree of impairment varies between the various types of T cells. For example, proliferative T cells are relatively insensitive to hypoxia, but very sensitive to reduced glucose, which may be related to the increase in IO response that we observe in tumors with a greater degree of hypoxia.
Conclusion:
Overall, we found that the nutrient composition of the tumor microenvironment has a strong influence on T-cell activity, especially in hypoxic tumor regions.
References:
[1] Makowski L, Chaib M, Rathmell JC. Immunometabolism: From basic mechanisms to translation. Immunol Rev. 2020;295(1):5-14. doi:10.1111/imr.12858
[2] Harcombe WR, Riehl WJ, Dukovski I, et al. Metabolic Resource Allocation in Individual Microbes Determines Ecosystem Interactions and Spatial Dynamics. Cell Rep. 2014;7(4):1104-1115. doi:10.1016/J.CELREP.2014.03.070
