Tumor-induced metabolic reprogramming and CD8+ T-cell exhaustion of the spleen

Motivation: Metastasis is the leading cause of cancer-related mortality worldwide. We must pave new avenues for cancer treatment by interrogating the pro-tumorigenic properties of the tumor macroenvironment. Goal(s): We seek to investigate how tumorigenesis metabolically impacts the spleen microenvironment and how it contributes to immune evasion. Approach: Proton magnetic resonance spectroscopy was used to identify aqueous spleen metabolites during tumorigenesis. Flow cytometric analyses were conducted to immunophenotype splenic CD8+ T cells and to quantify MDSC and T-cell frequencies. Results: Tumorigenesis induced common, distinct metabolite changes in mouse spleens. Flow cytometric analyses revealed splenic CD8-T-cell exhaustion and reduced cytotoxic T-cell effector function. Impact: Tumors drive metabolic spleen alterations that may contribute to reduced CD8+ T cells and their exhaustion even before reaching the tumor, contributing to immune suppression and poor prognosis. This may provide metabolism-targeted strategies to improve immune surveillance and immunotherapy.