Biology subjects

Ulloa-Navas, M. J.

Publications and source records attributed to Ulloa-Navas, M. J..

5 recordsLinked to original sources

bioRxiv2026

A Standalone PD-1 Chimeric Switch Receptor T-Cell Platform Expands the Therapeutic Window of PD-L1 Targeting in Solid Tumors

Programmed death-ligand 1 (PD-L1) is a promising therapeutic target owing to its broad expression on tumor cells and immunosuppressive myeloid cells within the tumor microenvironment (TME), providing an opportunity to target both cellular compartments. However, physiological PD-L1 expression in normal tissues poses a substantial risk of on-target/off-tumor toxicity, limiting the therapeutic window and clinical translation of PD-L1-targeted cellular therapies. Here, we developed a standalone programmed death-1 (PD-1) chimeric switch receptor (CSR) T-cell platform designed to preserve the therapeutic advantages of PD-L1 targeting while improving tumor-normal discrimination. Iterative receptor engineering, with antitumor activity and normal-cell reactivity evaluated as parallel selection criteria, identified two lead PD-1 CSR T-cell candidates. Compared with our previously developed antibody-based PD-L1 CAR T cells, the lead candidates retained potent PD-L1-specific cytotoxicity against tumor cells while exhibiting markedly reduced cytotoxicity against primary human small airway epithelial cells, astrocytes, renal epithelial cells, hepatocytes, and cardiomyocytes. They also efficiently eliminated PD-L1-positive immunosuppressive myeloid cells and mediated dual-compartment targeting of tumor and myeloid cells in three-dimensional (3D) multicellular tumor organoids. In vivo, both candidates suppressed tumor growth and prolonged survival in orthotopic breast cancer and patient-derived glioblastoma models after systemic and intracranial administration, respectively. Collectively, these findings establish PD-1 CSR T cells as a standalone therapeutic platform that expands the therapeutic window of PD-L1-targeted cellular therapy by preserving dual-compartment targeting of tumor and immunosuppressive myeloid cells while reducing normal-cell reactivity, providing a foundation for further clinical translation across solid tumors.

molecular biology↗

bioRxiv2026

Intracranial Targeting of Cholesterol Processing Reveals a Therapeutic Vulnerability that Reprograms Glioblastoma and Promotes Antitumor Immunity

Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation induced metabolic collapse as a promising therapeutic approach for GBM.

cancer biology↗

bioRxiv2025

Monocarboxylate transporter 2 is required for the maintenance of myelin and axonal integrity by oligodendrocytes

Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/632306v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@2b7b22org.highwire.dtl.DTLVardef@a111fdorg.highwire.dtl.DTLVardef@a410f5org.highwire.dtl.DTLVardef@1556e2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Single CAR-Dual target: Intracranial Delivery of Anti-PD-L1 CAR T Cells Effectively Eradicates Glioma and Immunosuppressive Cells in the Tumor Microenvironment.

With the goal to overcome the limited treatment options and poor prognosis of glioblastoma (GBM), we have developed a PD-L1-targeting CAR T cell therapy, MC9999. In vitro experiments with MC9999 CAR T cells derived from GBM patients exhibited potent, antigen-specific cytotoxicity against autologous tumor cells and immunosuppressive cells within the tumor microenvironment (TME). In an orthotopic GBM model using patient-derived brain tumor-initiating cells, the intracranial delivery of MC9999 CAR T cells eradicated established tumors and improved survival. Single-cell RNA sequencing indicated that MC9999 CAR T cells activate interferon pathways, leading to GBM cell apoptosis. Multi-immunohistochemistry confirmed localized PD-L1 expression on tumor cells and TME-residing macrophages, but not in neurons or glia in patient tissue. The local delivery of MC9999 CAR T cells may be a safe, effective approach for simultaneously targeting PD-L1-positive GBM and its immunosuppressive TME and a strategy to overcome immune evasion and enhance the therapeutic potency of CAR T cell therapy against GBM.

cancer biology↗

bioRxiv2021

Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson's Disease

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinsons disease (PD) - characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) - astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.

neuroscience↗