Biology subjects

Gabrilovich, D. I.

Publications and source records attributed to Gabrilovich, D. I..

3 recordsLinked to original sources

bioRxiv2026

Hydroperoxy-lipids Are Essential Yet Insufficient For Execution Of Ferroptosis

Cells with irreparable redox disbalance in membranes trigger a program of regulated death - ferroptosis. 15-lipoxygenase (LOX)-catalyzed accumulation of hydroperoxy-phosphatidyl-ethanolamines (HOO-PEs) has been associated with the execution of ferroptosis; yet, experimental proof of their sufficiency is lacking. Using the Fe-independent hydrophobic radical initiator, 2,2'-azobis(2,4-dimethyl)-valeronitrile (AMVN), we demonstrate that the accumulation of hydroperoxy-phospholipids (HOO-PLs) is necessary, but insufficient for driving ferroptosis. We further show that Fe-catalyzed decomposition of HOO-PLs into radical intermediates and oxidatively truncated (OxTr) electrophilic species, as well as the formation of protein adducts with OxTr electrophilic species are required for the completion of the ferroptotic program. Consequently, three types of agents - inhibitors of LOXs and other enzymatic generators of HOO-PLs, radical scavengers, and small-molecule nucleophiles - acting at different stages of lipid peroxidation during the ferroptotic program represent effective and specific ferroptosis regulators and potential therapeutic remedies.

biochemistry↗

bioRxiv2026

TMEM33 deletion potentiates anti-tumor CD8+ T cell immunity

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8+ T cell responses. Constitutive Tmem33-/- mice exhibited delayed melanoma tumor growth and increased CD8+ T cell infiltration. Antigen-specific CD8+ compartments in tumors of Tmem33-/- mice showed TCF-1+PD-1+ progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8+ T cells ex vivo, (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo-expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8+ T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8+ T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy. One sentence summaryTMEM33 intrinsically limits progenitor exhausted CD8+ T cells, scales anti-tumor responses and predicts melanoma patient survival.

immunology↗

bioRxiv2024

Neutrophil extracellular traps promote tumor chemoresistance to anthracyclines

The microenvironment plays an important role in promoting tumor cell chemoresistance, but the mechanisms responsible for this effect are not clear. Here, using models of multiple myeloma (MM) and solid cancers, we demonstrate a novel mechanism mediated by neutrophils, a major cell population in the bone marrow (BM), that protects cancer cells from chemotherapeutics. We show that in response to tumor-derived soluble factors, BM neutrophils release their DNA in the form of neutrophil extracellular traps (NETs). Cell-free DNA derived from NETs is then taken up by tumor cells via endocytosis and localizes to the cytoplasm. We found that both NETs and cell-free DNA taken up by tumor cells can bind anthracyclines, leading to tumor cell resistance to this class of chemotherapeutic agents. Targeting cell-free DNA with Pulmozyme or blocking NET formation with a PAD4 inhibitor abrogates the chemoprotective effect of neutrophils and restores sensitivity of tumor cells to anthracyclines.

cancer biology↗