Biology subjects

Wolf, Y.

Publications and source records attributed to Wolf, Y..

4 recordsLinked to original sources

bioRxiv2026

Spatially enforced engagement of PD-1⁺ T cells with AXL⁺ cells reprograms the tumor microenvironment and overcomes anti-PD-1 resistance

Background: AXL overexpression promotes tumor-cell plasticity, local immune suppression, and resistance to PD-1 blockade. Conventional anti-AXL and anti-PD-1 antibodies combinations act independently and do not ensure physical proximity between PD-1+ T cells and AXL+ cells within the immunosuppressive tumor microenvironment. Methods: To address this limitation, we developed a non-tandem, tetravalent IgG bispecific antibody designed to simultaneously engage PD-1 and AXL (BiTE-AXL/PD-1). Its antitumor activity was evaluated using in vitro functional assays and humanized and immunocompetent head and neck squamous cell carcinoma (HNSCC) models and compared with the combination of monospecific anti-AXL and anti-PD-1 antibodies. Spatial multiplex imaging was used to characterize treatment-associated changes in the tumor microenvironment of an anti-PD-1-resistant murine model. Results: BiTE-AXL/PD-1 enhanced T-cell activation, promoted AXL-dependent tumor-T-cell conjugation, and increased tumor-cell killing in vitro, outperforming the combination of the two monospecific antibodies. In humanized and immunocompetent HNSCC models, BiTE treatment significantly delayed tumor growth compared with the antibody combination and was well tolerated, with no overt toxicity. Spatial multiplex imaging revealed a shift from a fibroblast-dominated microenvironment characterized by exhausted CD8+ T cells toward dendritic-cell- and CD8+ T-cell-enriched niches associated with antitumor immune activity. Conclusion: BiTE-AXL/PD-1 promotes physical proximity between PD-1+ T cells and AXL+ cells, enhances antitumor immune responses, and remodels the immunosuppressive tumor microenvironment. These findings support PD-1/AXL bispecific targeting as a promising therapeutic strategy to overcome resistance to PD-1 blockade in HNSCC.

cancer biology↗

bioRxiv2025

Decoy Antibodies Block Extracellular HSP70, Prevent Self Signaling and Inhibit Melanoma Cell Survival

Melanoma cells actively secrete melanosomes-large, extracellular vesicles (EVs) enriched with oncogenic factors that reprogram the tumor microenvironment, enhance self-signaling, and promote tumor growth. Despite their abundance and immunogenic potential, humoral responses to melanoma-derived melanosomes remain unexplored. Here, we identify a novel immune surveillance mechanism in which melanosome-elicited decoy antibodies target melanoma-derived melanosomes by binding to the extracellular form of heat shock protein 70 (HSP70), a chaperone broadly implicated in cancer cell survival and stress adaptation. Anti-HSP70 decoy antibodies potently and effector-independently inhibit growth and survival of both murine and human melanoma cells and suppress key transcriptional programs involved in proliferation, cytoskeletal dynamics, and metabolism. In a preclinical B16 melanoma model, prophylactic administration of decoy monoclonal antibodies Mel322-34 and Mel321-35 conferred significant survival benefits of 27% and 48%, respectively. Strikingly, anti-HSP70 antibodies were enriched in the sera of melanoma patients achieving complete responses to immune checkpoint blockade, in contrast to non-responders with progressive disease. Collectively, our findings uncover a novel EV-antibody axis as a promising avenue to block cancer-promoting signaling pathways. Decoy autoantibodies targeting the extracellular form of HSP70 advance the understanding of tumor-intrinsic vulnerability and promote biomarker-driven immunotherapy in melanoma.

immunology↗

bioRxiv2019

{-}{-}{-}{-}{-}Polyglutamine-related aggregates serve as a potent antigen source for cross presentation by dendritic cells

Protective MHC-I dependent immune responses require an overlap between repertoires of proteins directly presented on target cells and cross-presented by professional antigen presenting cells (APC), specifically dendritic cells (DCs). How stable proteins that rely on DRiPs for direct presentation are captured for cell-to-cell transfer remains enigmatic. Here we address this issue using a combination of in vitro and in vivo approaches involving stable and unstable versions of ovalbumin model antigens displaying DRiP-dependent and -independent antigen presentation, respectively. Apoptosis, but not necrosis of donor cells was found associated with robust p62-dependent global protein aggregate formation and captured stable proteins permissive for DC cross-presentation. Potency of aggregates to serve as antigen source was directly demonstrated using polyglutamine-equipped model substrates. Collectively, our data implicate global protein aggregation in apoptotic cells as a mechanism that ensures the overlap between MHC-I epitopes presented directly or cross-presented by APC and demonstrate the unusual ability of DC to process stable protein aggregates.\n\nSummaryProtective T cell immunity relies on the overlap of the antigen repertoire expressed by cells and the repertoire presented by dendritic cells that are required to trigger naive T cells. We suggest a mechanism that contributes to ensure this antigenic overlap. Our findings demonstrate that upon apoptosis stable proteins are aggregated in p62-dependent pathway and that dendritic cells are capable to efficiently process these aggregates to retrieve antigens for T cell stimulation.

cell biology↗

bioRxiv2017

Diverse functions of closely homologous actin isoforms are defined by their nucleotide, rather than their amino acid sequence.

{beta}- and {gamma}-cytoplasmic-actin are nearly indistinguishable in their amino acid sequence, but are encoded by different genes that play non-redundant biological roles. The key determinants that drive their functional distinction are unknown. Here we tested the hypothesis that {beta}- and {gamma}-actin functions are defined by their nucleotide, rather than their amino acid sequence, using targeted editing of the mouse genome. Although previous studies have shown that disruption of {beta}-actin gene critically impacts cell migration and mouse embryogenesis, we demonstrate here that generation of a mouse lacking {beta}-actin protein by editing {beta}-actin gene to encode {gamma}-actin protein, and vice versa, does not affect cell migration and/or organism survival. Our data suggest that the essential in vivo function of {beta}-actin is provided by the gene sequence independent of the encoded protein isoform. We propose that this regulation constitutes a global \"silent code\" mechanism that controls the functional diversity of protein isoforms.

cell biology↗