mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow

Abstract

Novel therapies for multiple myeloma (MM) aim to engage antitumor functions of T cells. However, evidence indicates these functions are limited within the bone marrow (BM) environment. This is relatively hypoxic in health, and studies indicate widespread hypoxia in MM. In this study, CD8+ T-cell responses to stimulation were assessed under hypoxia, which identified that activation, proliferation, and interferon-gamma (IFN-γ) secretion were profoundly suppressed, while cytotoxicity and tumor necrosis factor-α (TNF-α) expression were unaffected. These changes occurred alongside decreased mechanistic target of rapamycin (mTOR) activity and expression of c-Myc, which drives T-cell metabolic reprogramming upon stimulation. Consistently, hypoxic CD8+ T cells demonstrated decreased activation-induced glycolysis and mitochondrial glutamine oxidation. Mechanistically, this was linked to elevated BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) expression under hypoxia, and reciprocally decreased abundance of its interaction partner, Ras homolog enriched in brain (Rheb), an important mTOR activator. Assessment of BCMA×CD3 bispecific antibody activity confirmed impaired capacity to elicit CD8+ T-cell activation, IFN-γ expression, proliferation, and altered memory differentiation under hypoxia, although initial target cell killing was unaffected. Finally, assessment of BM CD8+ T cells from patients with MM identified decreased proliferation, c-Myc, and Rheb expression compared with peripheral blood cells, alongside elevated BNIP3, confirming mechanistic features of hypoxic exposure in this environment. Taken together, the findings indicate potential for BM hypoxia to influence efficacy of T cell-directed therapies for MM.