Browsing by Author "Lieberman, Mackenzie M."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity
    (Springer Nature, 2024) Holling, G. Aaron; Chavel, Colin A.; Sharda, Anand P.; Lieberman, Mackenzie M.; James, Caitlin M.; Lightman, Shivana M.; Tong, Jason H.; Qiao, Guanxi; Emmons, Tiffany R.; Giridharan, Thejaswini; Hou, Shengqi; Intlekofer, Andrew M.; Higashi, Richard M.; Fan, Teresa W. M.; Lane, Andrew N.; Eng, Kevin H.; Segal, Brahm H.; Repasky, Elizabeth A.; Lee, Kelvin P.; Olejniczak, Scott H.; Medicine, School of Medicine
    Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
  • Thumbnail Image
    Item
    Endogenous CD28 drives CAR T cell responses in multiple myeloma
    (bioRxiv, 2024-04-09) Lieberman, Mackenzie M.; Tong, Jason H.; Odukwe, Nkechi U.; Chavel, Colin A.; Purdon, Terence J.; Burchett, Rebecca; Gillard, Bryan M.; Brackett, Craig M.; McGray, A. J. Robert; Bramson, Jonathan L.; Brentjens, Renier J.; Lee, Kelvin P.; Olejniczak, Scott H.; Medicine, School of Medicine
    Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.