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 modeling² 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.

Conclusions 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