Biology subjects

Schuster, V. P.

Publications and source records attributed to Schuster, V. P..

3 recordsLinked to original sources

bioRxiv2026

Self-antigen disrupts cDC1 mediated antitumor responses

Conventional dendritic cells navigate complex tissues and sample peripheral antigens, balancing immune suppression and activation to achieve tissue homeostasis. However, it remains unclear how an individual dendritic cells reconciles co-incident signals from immunological opposing antigens within the tissue or tumor microenvironment, where tolerogenic self-antigen and immunogenic tumor antigen or microbes coexist. Here, using complementary in vivo fluorescent reporter systems, high-resolution imaging and endosomal profiling, we simultaneously tracked uptake, intracellular processing and cross-presentation of cutaneous self, tumor and microbial antigens in murine skin tissue, tumors and draining lymph nodes. We find that a substantial fraction of dendritic cells acquire antigen from multiple sources and that localization within endosomal compartments is dictated by antigen source. Notably, type 1 conventional dendritic cells that co-process self and tumor antigen represent a significant proportion of tumor antigen-bearing dendritic cells in the tumor and tumor draining lymph node. These dual-antigen loaded dendritic cells display a diminished capacity to prime tumor-specific CD8+ T cells and a marked reduction in tumor derived peptide presented on surface MHCI, while cross-priming of self-antigen specific T cells is significantly increased. These changes occur despite equivalent or greater tumor antigen uptake relative to self-antigen and high expression of surface MHCI and costimulatory molecules. Together, these data support a model in which multiantigen processing within dendritic cells can bias peptide loading away from tumor-derived epitopes, thereby limiting tumor-specific cross-priming. Modulating the antigenic context of the tumor microenvironment or endosomal routing after antigen uptake may therefore represent a strategy to restore effective dendritic cell-mediated antitumor immunity.

immunology↗

bioRxiv2026

A Framework for Comparing Mouse Neoantigen Immunogenicity

Cytotoxic CD8+ T cell responses targeting tumor neoantigens are critical for immunotherapy efficacy and are widely studied across different preclinical mouse tumor models. Defined neoantigens are commonly introduced to enable tracking of tumor-specific T cells; however, variation in neoantigen choice may yield immune phenotypes attributable to differences in neoantigen immunogenicity, complicating interpretation of tumor-intrinsic mechanisms. Here, we determined the relative immunogenicity of a set of 25 commonly used mouse tumor-derived and model neoantigens to facilitate comparison of neoantigens across studies. We found that in silico predicted major histocompatibility complex (MHC) binding affinity poorly stratified in vivo immunogenicity. In contrast, experimental measurement of peptide-MHC complex stability (Koff), more so than measured affinity (KD), closely correlated with the relative magnitude of neoantigen-targeted vaccine responses in vivo. Thus, we report the relative stability of a known set of commonly used neoantigens as a reference and provide a simple method to benchmark novel neoantigens against this library. This framework will allow contextualization of the level of immunogenicity of newly identified neoantigens and aid in comparative interpretation of tumor-immune phenotypes across studies.

cancer biology↗

bioRxiv2025

Contextual control of CD8+ T cell priming by dendritic cell subsets in tumor and inflammatory microenvironments

Conventional dendritic cells orchestrate adaptive immunity by trafficking peripheral antigens to draining lymph nodes and presenting peptide-MHC complexes to prime naive T cells. Migratory and lymph node resident conventional dendritic cell subsets occupy distinct anatomical niches and have been shown to shape T cell activation in a variety of immunologic contexts including infection, vaccination and cancer. How peripheral tissue context and dendritic cell subset specific transcriptional programs collaborate to determine CD8+ T cell priming remains incompletely defined. Using fluorescent antigen, we tracked antigen distribution, dendritic cell transcriptional programming, and functional cross-presentation across tumor, inflammatory, and steady state tissue contexts. We find that skin tumor antigen is more widely distributed amongst draining lymph node conventional dendritic cells than skin antigen derived from either steady state or inflamed skin tissue. Comparing across dendritic cell subsets, migratory type 1 dendritic cells display higher expression of MHCI antigen presentation machinery and genes associated with cross-presentation compared with lymph node resident type 1 dendritic cells in tumor and inflamed tissue contexts. Similarly, they exhibited superior per-cell cross-presentation and stronger induction of naive CD8+ T cell responses. We find that both antigen access in the lymph node and context-specific cross-presentation efficiency together predict the magnitude and quality of CD8+ T cell priming. These results identify migratory dendritic cells, particularly type 1, as central mediators of antitumor CD8+ T cell responses and support therapeutic strategies that augment the efficiency of resident dendritic cell cross-presentation.

immunology↗