Biology subjects

Cios, A.

Publications and source records attributed to Cios, A..

3 recordsLinked to original sources

bioRxiv2026

CMTM6-Silencing Microbial Immunotherapy Reprograms PDAC Tumors and Restores T-cell Function

Despite recent advances in immunotherapy for advanced malignancies, Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to current immunotherapy due to dense fibrosis, limited antigen presentation, and myeloid-driven immune suppression. Here we report the tumor-targeting, immune remodeling, and safety profiles of the attenuated Salmonella enterica serovar Typhimurium strain CRC2631, and of iSTORM, a next-generation derivative engineered for tumor-localized CMTM6 silencing. CRC2631 preferentially colonizes orthotopic and genetically engineered PDAC tumors, with enrichment in primary lesions and metastases. Tumor-localized CRC2631 induces chemokine and adhesion programs consistent with leukocyte recruitment, increases intratumoral activated T-cell fractions, and triggers transcriptional signatures aligned with innate sensing, interferon signaling, antigen-processing and presentation, and apoptosis programs. iSTORM extends this platform by delivering CMTM6-targeting shRNA to modulate a PD-L1-stabilizing, myeloid-associated immune-evasion programs within tumor-colonized tissue. Compared with CRC2631, iSTORM increases intratumoral CD8+ T cells, shifts T-cell state toward activation with reduced exhaustion-prone features, strengthens antigen-presentation programs, and achieves deeper tumor control. A lyophilized formulation preserves immune remodeling while improving deployability. Mechanistically, glycan arrays and functional studies support mannose-rich glycan-guided tumor engagement. iSTORM toxicity studies, including systemic cytokine, hematologic, blood chemistry, and lethality demonstrate a favorable safety profile. Collectively, these findings establish iSTORM as a safe, programmable, CMTM6-silencing microbial immunotherapy platform that selectively targets and penetrate PDAC tumors to unleash anti-tumor immune activities. What is already known on this topicPDAC is highly resistant to immune checkpoint blockade because dense stroma and myeloid-dominated suppression prevent effective T-cell infiltration; attenuated Salmonella strains can selectively colonize tumors but first-generation agents showed limited efficacy and safety concerns. What this study addsThis study defines CRC2631/iSTORM as a tumor-selective microbial immunotherapy that exploits surface-exposed, mannose-rich N-glycans to colonize PDAC, delivers CMTM6 silencing, and restores CD8+ T-cell activation and tumor control in models resistant to PD-1 blockade immunotherapy. How this study might affect research, practice or policyThese findings provide a mechanistic blueprint for glycan-guided, CMTM6-targeted bacterial "living drugs," support rational combination strategies for deepening therapeutic effect, and establish a lyophilized, biocontained platform that could be developed into scalable microbial immunotherapies for PDAC and other immunologically cold solid tumors.

cancer biology↗

bioRxiv2025

Pancreatic tumor microenvironment reprogramming via alloantigen-expressing virotherapy elicits tumor rejection and improves immunotherapy response

Pancreatic ductal adenocarcinoma (PDAC), the most common malignant type of pancreatic cancer, is characterized by a dense desmoplastic stroma, low neoantigen burden, and a highly immunosuppressive tumor microenvironment (TME), which severely limit cytotoxic T-cell infiltration and the efficacy of immune therapies. Here, we present a novel strategy harnessing acute transplant rejection mechanisms by employing a recombinant oncolytic rVMG vector engineered to express the murine H-2Kk MHC class I alloantigen (rVMG-H-2Kk), thereby inducing tumor-specific antigenic mismatch responses. In vitro, rVMG-H-2Kk exhibited strong replication and cytolytic activity while inducing cell surface expression of both H-2Kk and endogenous H-2Kb, in addition to upregulation of antigen presentation genes ({beta}2-microglobulin, Tap1, and Tapbp). In two independent immunocompetent PDAC models, intratumoral and systemic delivery of rVMG-H-2Kk delayed tumor progression and prolonged survival. Multiplex immunohistochemistry and immunophenotyping revealed substantial TME remodeling, marked by increased effector T-cell infiltration, regulatory T-cell depletion, and reduced fibrosis. Spatial transcriptomics further showed compartment-specific immune activation and epithelial metabolic reprogramming, corroborating with enhanced tumor immunogenicity. Despite these effects, rVMG-H-2Kk also induced compensatory immunosuppressive pathways, including upregulation of antiviral response genes and immune checkpoint receptors such as PDL-2. Importantly, combination therapy with rVMG-H-2Kk and murine checkpoint blockade (anti-PD-1 and anti-CTLA-4) drastically improved survival than checkpoint blockade alone. Strikingly, surviving mice resisted tumor rechallenge, indicating the establishment of durable antitumor memory. Collectively, these findings establish rVMG-H-2Kk as a novel immunotherapeutic platform capable of converting immune-cold tumors into immune-hot, sensitizing tumors to immune checkpoint inhibitors, and establishing durable antitumor immunity in PDAC. One Sentence SummaryOncolytic virus-based delivery of an alloantigen improves antitumor immunity and synergizes with immune checkpoint inhibitors in pancreatic cancer. Significance statementDelivery of murine alloantigens via an engineered oncolytic vesiculovirus, combined with immune checkpoint blockade, overcomes immunosuppressive barriers and establishes durable antitumor immunity in PDAC.

cancer biology↗

bioRxiv2025

Repeat Systemic Delivery of Cross-Neutralization Resistant Synthetic Vesiculoviruses Immunomodulates the Tumor Microenvironment

The clinical efficacy of systemic oncolytic virotherapy (OV) is constrained by the rapid development of neutralizing antibodies (nAbs), which prevent repeat systemic administration, a critical barrier to sustained anti-tumor immunity. Vesiculoviruses offer potent oncolytic and immunogenic potential. However, leveraging their serological diversity for repeat dosing remains unexplored. We generated a library of chimeric vesiculovirus vectors incorporating glycoproteins from less well characterized vesiculovirus species. We evaluated vector replication, infectivity, interferon (IFN) responses, and oncolysis in vitro, alongside assessments of neutralization resistance using patient sera, monoclonal antibodies, and in silico structural modeling. In vivo studies assessed tumor delivery, immune activation, and therapeutic efficacy following intravenous administration. The vesiculovirus library exhibited broad tumor infectivity, distinct IFN-stimulatory profiles, and variable oncolytic activity. Neutralization assays and computational modeling identified serological distinctness across vectors, driven by hypervariable glycoprotein epitopes, enabling evasion of cross-neutralizing antibodies. Tumor delivery and anti-tumor immunity were preserved despite humoral barriers. Incorporating tumor-associated antigens (TAAs) further amplified anti-tumor responses, even in the context of anti-viral memory. Sequential administration of distinct vesiculovirus vectors induced robust immune activation and improved survival in a B16-OVA-IFNAR-/- model. Our findings establish a glycoprotein-diverse vesiculovirus platform capable of overcoming humoral immunity, enabling repeat intravenous dosing and sustained engagement of the tumor microenvironment. This strategy advances the field of oncolytic virotherapy by addressing a major translational barrier and lays the groundwork for future clinical studies integrating multi-vector, multi-dose immunovirotherapy with immune checkpoint blockade. One Sentence SummaryA glycoprotein-engineered vesiculovirus platform circumvents neutralizing antibodies, enabling repeat intravenous dosing and sustained anti-tumor immunity in preclinical models.

molecular biology↗