Biology subjects

Hsu, Y.-S.

Publications and source records attributed to Hsu, Y.-S..

3 recordsLinked to original sources

bioRxiv2026

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis

Cardiac fibrosis is causally linked to heart failure progression and survival. Currently, there are no approved treatments that directly target cardiac fibrosis. Recent studies have identified a subset of activated cardiac fibroblasts distinct from myofibroblasts that are marked by fibroblast activation protein (FAP) expression, emerge in the injured and diseased heart through inflammatory signaling, and contribute to fibrosis. Using a genetic mouse model, we demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE(R) molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced remodeling, and increased scar size. FAP BiTE(R) molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg; and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Mechanistically, we reveal that IFNg; signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE(R) molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE(R) molecules and inform the design of the next generation of therapeutics.

immunology↗

bioRxiv2024

Rational protein engineering to enhance MHC-independent T cell receptors

Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity against cancer, however remain limited in their scope and long-term efficacy. Emerging data suggest that dysregulated CAR-driven T cell activation causes T cell dysfunction and therapeutic failure. To re-engage the endogenous T cell response, we designed hybrid MHC-independent T cell receptors (miTCRs) by linking antibody variable domains to TCR constant domains. While functional, we observed stark differences in miTCR-driven T cell function that were dependent on receptor orientation. Using predictive structural modeling, we observed significant biochemical conflicts at the hybrid variable-constant domain interface. To overcome this, we performed iterative sequence modifications and structural modeling to design a panel of miTCR variants predicted to have improved interface stability. Functional screening nominated a variant with superior efficacy to all other miTCRs as well as a standard CAR against high burdens of leukemia. Statement of SignificanceImproving the durability of engineered T cell immunotherapies is critical to enhancing efficacy. We used structure-informed design to evolve MHC-independent T cell receptors that drive improved tumor control. This work underscores the central role of synthetic receptor structure on T cell function and provides a framework for improved receptor engineering.

immunology↗

bioRxiv2023

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction

Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 improves CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3. SummaryChronic stimulation of CARs containing the 41BB costimulatory domain leads to a novel state of T cell dysfunction that is distinct from T cell exhaustion.

immunology↗