Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.

Abstract

T cells are pivotal to cancer immunotherapy, yet chemotherapy may erode their fitness. Using a single-cell technique, we show that exposure to two widely used chemotherapeutic agents, 5-FU (5-fluorouracil) and cisplatin, induces non-synonymous mitochondrial DNA (mtDNA) mutations in T cells. Notably, nearly all detected mtDNA mutations are transition mutations. Like the effects observed in genomic DNA mutations, the impacts of mtDNA mutations in T cells appear to be random. Some T cells with mtDNA mutations concentrate in clusters associated with gene markers, while others do not. Additionally, several mtDNA mutations are found in the fraction of treated T cells with low mitochondrial activity, suggesting their potential effect on mitochondrial function. Importantly, mtDNA mutations are detected in tumor-infiltrating T cells from patients with colorectal cancer who received chemotherapy. Our findings uncover an unappreciated consequence of chemotherapy on T cell mitochondria, and these results raise concerns about administering immunotherapy and chemotherapy concurrently.