Browsing by Author "Brackett, Craig M."

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    Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression
    (Elsevier, 2024-02-10) Tzetzo, Stephanie L.; Kramer, Elliot D.; Mohammadpour, Hemn; Kim, Minhyung; Rosario, Spencer R.; Yu, Han; Dolan, Melissa R.; Oturkar, Chetan C.; Morreale, Brian G.; Bogner, Paul N.; Stablewski, Aimee B.; Benavides, Fernando J.; Brackett, Craig M.; Ebos, John M. L.; Das, Gokul M.; Opyrchal, Mateusz; Nemeth, Michael J.; Evans, Sharon S.; Abrams, Scott I.; Medicine, School of Medicine
    Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.
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    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.