Intercellular nanotube-mediated mitochondrial transfer enhances T-cell metabolic fitness and antitumor efficacy

Mitochondrial loss and dysfunction drive T cell exhaustion and represent major barriers to successful T cell immunotherapies. We found that mesenchymal stromal cells (MSC) establish nanotubular connections with T cells in a TLN2-dependent manner and leveraged these intercellular highways to supply new mitochondria to CD8+ T cells. Acquisition of MSC mitochondria increased T cell basal mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, tumor-specific CD8+ T cells with donated mitochondria expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared to CD8+ T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. To unravel the mechanisms behind mitochondrial transfer we performed RNA sequencing on CD8+ T cells that acquired donor mitochondria (MitoPositive), or did not acquire donor mitochondira (MitoNegative) directly after after co-culture (0hr timepoint). Overall design: conditions: control, Mito_positive, Mito_negative, three replicates each