Biology subjects

Hector, E.

Publications and source records attributed to Hector, E..

3 recordsLinked to original sources

bioRxiv2026

Antibody maturation in germinal centers selects mutants based on BCR-antigen bond mechanical resistance

Antibody maturation in germinal centers (GCs) is traditionally viewed as a process that enhances antigen-binding affinity of B cell receptors (BCR). However, recent studies challenge this paradigm, revealing no systematic antibody affinity improvement during GC selection. Here, we investigate whether mechanical resistance of antibody-antigen bonds, rather than affinity, is the selective parameter driving GC maturation. Using biolayer interferometry measurements for assessing affinity and laminar flow chamber for mechanical resistance, we analyzed three lineages of mouse antibodies generated after immunization with ovalbumin. While affinity changes were heterogeneous, ranging from gains to losses across lineages, mechanical resistance consistently increased after maturation. Bond lifetimes under physiological forces (10-70 pN) converged to similar values across lineages, suggesting a selective pressure for mechanical stability. Functionally, NK cell activation in a surrogate in vitro ADCC assay correlated with bond lifetimes under force, but not with affinity. This indicates that lymphocytes are sensitive to the mechanical stability of antibody-antigen interactions, which may underlie GC selection. Our findings reconcile antibody maturation with the idea of enhanced binding, while aligning with the role of mechanical forces in B cell signaling and antigen uptake. These insights provide a framework for understanding GC biology and may inform the design of therapeutic antibodies.

immunology↗

bioRxiv2025

SeQuoIA: a single-cell BCR sequencing analysis pipeline for tracking selection mechanisms in germinal centres

Germinal centres (GCs) are specialized structures where B cells undergo iterative steps of B-cell receptor (BCR) somatic hypermutation and selection of best antigen binders in a darwinian-like fashion. The accelerated evolutionary process leads to the production of high-affinity antibodies that are crucial for robust and long-term humoral immunity. Within this frame, single-cell BCR sequencing analysis is a method of choice to track GC B cell dynamics as somatic mutations can be utilised as an in vivo molecular tracer. Herein, we present SeQuoIA, a start-to-finish pipeline for the analysis of BCR repertoire sequencing data at the single-cell level, including improved clonotype assignment and phylogeny reconstruction. Most importantly, we introduce a new method for the inference of BCR-driven selection pressure based on somatic mutation patterns, that was validated with biological data. With this pipeline, we explored public datasets and proposed new selection mechanisms in GCs. SignificanceOur pipeline should contribute to a better understanding of the basic biology of GC dynamics, and potentially help in laboratory animal usage reduction. Clinical applications could include assessment of vaccine efficacy, monitoring of B cell anti-tumoral responses, and identification of BCR-mediated processes in B cell lymphomas.

immunology↗

bioRxiv2022

Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors

It is currently accepted that activated cancer-associated fibroblasts (CAF) participate in T cell exclusion from tumor nests, but it remains unclear how they promote barrier phenotypes, and whether specific subsets are involved. Here, using single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors, we identify four main CAF populations, of which only two are associated with T cell exclusion: (i) MYH11+SMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+SMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both CAF populations show a contractility phenotype together with dense and aligned matrix fiber deposition compared to the T cell-permissive CAF. Yet they express distinct matrix genes, including COL4A1/COL9A1 (MYH11+SMA+ CAF) and COL11A1/COL12A1 (FAP+SMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCEThe cellular and molecular programs driving T cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to develop new strategies targeting T cell-excluding CAF.

cancer biology↗