mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.
Fulton-Ward, Taylor Gudgeon, Nancy Thirlwell, Isaac Bishop, Emma Louise Marzullo, Bryan Giles, Hannah Victoria McIlroy, Graham Ferguson, Paul Kishore, Bhuvan Rogers, Kate
Fulton-Ward, Taylor
Gudgeon, Nancy
Thirlwell, Isaac
Bishop, Emma Louise
Marzullo, Bryan
Giles, Hannah Victoria
McIlroy, Graham
Ferguson, Paul
Kishore, Bhuvan
Rogers, Kate
Abstract
Novel therapies for multiple myeloma aim to engage anti-tumour functions of T cells. However, evidence indicates these functions are limited within the bone marrow environment. This is relatively hypoxic in health and studies indicate widespread hypoxia in multiple myeloma. 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, whilst cytotoxicity and tumour necrosis factor-alpha (TNF-α) expression were unaffected. These changes occurred alongside decreased 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 BNIP3 expression under hypoxia and reciprocally decreased abundance of its interaction partner, Rheb, an important mTOR activator. Assessment of BCMAxCD3 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 bone marrow CD8+ T cells from multiple myeloma patients identified decreased proliferation, c-Myc and Rheb expression compared to peripheral blood cells, alongside elevated BNIP3, confirming mechanistic features of hypoxic exposure in this environment. Taken together, the findings indicate potential for bone marrow hypoxia to influence efficacy of T cell-directed therapies for multiple myeloma.
Date
2025-09-12
Type
Article
Subject
Multiple Myeloma, Immunotherapy, Haematology
Collections
Citation
Fulton-Ward T, Gudgeon N, Thirlwell I, Bishop EL, Marzullo B, Giles H, McIlroy G, Ferguson P, Kishore B, Rogers K, Alfasi N, Wong T, Aytain S, Tennant DA, Pratt G, Dimeloe S. mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow. Blood Adv. 2025 Dec 9;9(23):6175-6188. doi: 10.1182/bloodadvances.2025016439.
Journal / Source Title
Blood Advances
DOI
10.1182/bloodadvances.2025016439
PMID
40938732
Publisher
American Society of Hematology
Publisher’s URL
https://pubmed.ncbi.nlm.nih.gov/40938732/