Biology subjects

Hornburg, M.

Publications and source records attributed to Hornburg, M..

3 recordsLinked to original sources

bioRxiv2026

Systemic neoantigen-specific T cells reveal central determinants of PD-(L)1 blockade efficacy

The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I-restricted and 21,453 HLA-II-restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti-PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of tumor mutational burden. Patients mounting coordinated CD4 and CD8 responses experienced improved progression-free survival. Tumors from CD8 responders displayed immune signatures indicative of both T cell priming and effector functions. Circulating neoantigen-specific CD8 T cells recognized endogenously processed antigens, trafficked to tumors, and selectively expanded under therapy while retaining CD28, CD226, and CXCR3 expression. These findings identify coordinated, functionally engaged neoantigen-specific T cell responses as central determinants of PD-(L)1 efficacy.

cancer biology↗

bioRxiv2025

Recurrent RNA-lipoplex vaccination is required to sustain functional tumor-infiltrating neoantigen-specific CD8 T cells and therapeutic efficacy

Cancer vaccines induce durable, polyepitopic T cell responses, and show promising clinical benefit in adjuvant settings, yet they are largely ineffective in advanced disease. Using a clinically relevant RNA-lipoplex vaccine, we investigated the efficacy constraints in a preclinical model. Vaccination remodeled the tumor microenvironment (TME), increasing T cell infiltration and promoting a proinflammatory myeloid compartment. This was associated with complete regression of smaller, immature tumors, but only delayed growth of larger, established tumors. While vaccine-induced T cells were long-lived and functional in peripheral tissues, intratumoral T cells declined rapidly in abundance, diversity, and function, reverting to a prevaccine-like state. scRNA-seq suggested that this was driven by a pro-apoptotic program, with surviving T cells showing signatures of cellular stress and impaired activation. Importantly, recurrent vaccination replenished functional T cells in the TME and enhanced efficacy. These findings highlight the importance of optimizing vaccine schedules and tailoring therapeutic strategies to tumor stage.

immunology↗

bioRxiv2025

Cross-competition shapes CD8+ T cell hierarchies and differentiation after RNA vaccination

Short SummaryImmunodominance is a universal feature of adaptive immunity that constrains T cell expansion, clonal diversity and breadth resulting in a narrowly focused T cell response. While observed across diverse priming settings and vaccine platforms, the influence of immunodominance on T cell phenotype remains unclear. Using an mRNA lipoplex vaccine encoding multiple antigens to study how immunodominance influences CD8+ T cell fate, we found that dominant CD8+ T cell responses alter the magnitude and phenotype of subdominant responses through peptide-MHC-I stability-mediated T cell cross-competition. Dominant CD8+ T cell responses preferentially acquired markers associated with terminal differentiation and cytotoxic function, while sub-dominant responses adopted memory-precursor and stem-like features. Removal of dominant responses allowed increased expansion of sub-dominant T cell responses and adoption of terminally differentiated effector phenotypes. These findings reveal that immunodominance dynamically shapes the magnitude, breadth and differentiation of CD8+ T cell responses and highlights opportunities to fine-tune T cell responses for therapeutic vaccination.

immunology↗