Biology subjects

Nejatfard, A.

Publications and source records attributed to Nejatfard, A..

4 recordsLinked to original sources

bioRxiv2025

A Transient Immunostimulatory Niche Synergizes Adoptive and Endogenous Immunity for Enhanced Tumor Control

Adoptive Cell Therapy (ACT) has achieved curative responses in hematological malignancies, yet its translation to solid tumors remains limited by manufacturing bottlenecks, systemic toxicities, and poor T-cell infiltration and persistence within the immunosuppressive tumor microenvironment (TME). Here, we report the development and mechanism of ACTIVATE (Adoptive Cell Therapy and Immunostimulatory Vehicle for Anti-Tumor Efficacy), which leverages an injectable hydrogel depot technology that forms a transient inflammatory niche for localized co-delivery of adoptive T cells and native cytokines. By tuning cytokine identity, ACTIVATE enables precise modulation of T-cell expansion, effector function, and interaction with endogenous immune networks. We found that enhancing T-cell proliferation alone is insufficient to drive robust tumor control; instead, coordinated engagement of both adoptive and endogenous immune responses is critical for durable anti-tumor efficacy. In vivo, this orchestration via ACTIVATE led to enhanced infiltration and cytotoxicity of both adoptive and host-derived immune effectors, while driving robust recruitment and activation of T cells, B cells, dendritic cells, and macrophages in the tumor-draining lymph nodes. This local immune activation can further reshape the TME, promoting antigen presentation and suppressing immunoregulatory populations, thus enhancing anti-tumor efficacy in murine melanoma and lymphoma models. These findings establish ACTIVATE as a modular platform for orchestrating coordinated immune responses to improve ACT outcomes in solid tumors.

immunology↗

bioRxiv2025

Spatially Tuned Localization of Interleukins and OX40 Agonists EnhancesSynergistic Anti-Tumor Immunity

Advances in immunotherapy have revolutionized the current standard of care for cancer patients, but unfortunately, most approaches still fail to mount a robust anti-cancer effect. This is in part due to a highly immunosuppressive tumor microenvironment which has developed bio-orthogonal mechanisms of immune escape. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune related adverse effects and toxicity. Enabling potent combination immunotherapies requires administering these immune agonists in a way that more closely resembles the endogenous cancer immunity cycle, a tightly regulated sequence of cues in both space and time. Here, we explore the ability of an injectable hydrogel depot to enable the rational localization of potent immunotherapeutic cytokines (IL-12, IL-2) and antibodies (OX40a). We hypothesized that selectively altering the biodistribution of these cargo would enable tolerable and synergic anti-cancer combinations, so we leveraged a previously characterized injectable polymer-nanoparticle (PNP) hydrogel system to deliver these agonists either intratumorally (IT) or peritumorally (PT). Using in vivo imaging, we demonstrated that site of administration is critical to redistributing cargo to either the tumor or tumor draining lymph node (tdLN). Further, we demonstrated that the targeted localization of cytokine and antibody therapies synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and altered cellular phenotypes in these microenvironments. This approach thus represents a crucial new strategy for basic cancer immunology and materials-based immuno-engineering research while improving therapeutic efficacy.

bioengineering↗

bioRxiv2021

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates

Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we sought to understand the mechanism associated with Dfm1s actions and found that Dfm1s conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that derlin rhomboid pseudoproteases employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.

cell biology↗

bioRxiv2020

Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors

Phosphatidylethanolamine made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.

cell biology↗