Biology subjects

Guille, A.

Publications and source records attributed to Guille, A..

4 recordsLinked to original sources

bioRxiv2026

Multiomic dissection of HR+/HER2- invasive lobular breast carcinoma reveals mobilized yet dysfunctional anti-tumor immunity shaped by tumor-stroma crosstalk and impaired antigen presentation

ContextImmunotherapy based on immune checkpoint inhibitors (ICI) revolutionized the treatment of triple-negative (TN) breast carcinomas (BC), but remains more challenging in HR+/HER2- BCs. Because invasive lobular carcinomas (ILC) generally exhibit low immune infiltration, ICIs were largely overlooked in this pathological type. The only clinical trial of ICIs dedicated to ILCs showed disappointing results, notably in HR+/HER2- cases. The immune landscape of HR+/HER2- ILCs has been poorly described. High level of tumor-infiltrating lymphocytes (TIL) was associated with worse prognosis in HR+/HER2- ILCs. A better characterization of the immune landscape of HR+/HER2- ILCs could clarify the poor efficiency of ICIs and the negative prognostic value of TILs, and reveal complementary targets able to increase immunotherapy efficiency. MethodWe comprehensively characterized the immune landscape of HR+/HER2- ILCs, comparatively to HR+/HER2- invasive ductal carcinomas (IDC), by applying multi-omics and multi-scale analysis (gene expression at the bulk and single-cell levels, and protein-based spatial analysis) to clinical samples. ResultsWhile the overall level of immune infiltration was comparable between both pathological types, the quality of immune infiltrate differed markedly. Comparatively to HR+/HER2- IDCs, HR+/HER2- ILCs were enriched in immune cells and tertiary lymphoid structures with anti-tumor potential, presented more spatial proximity between cancer cells and CD8+ cytotoxic T cells, and stronger theorical vulnerability to ICIs. However, in HR+/HER2- ILCs, anti-tumor response was defective; CD8+ cytotoxic T cells failed to fully unleash their cytotoxic function and CD4+ helper T cells evidenced a pro-tumoral and naive phenotype. Furthermore, antigen-presenting compartment was defective, altogether embedded in a stronger immunosuppressive environment, enriched in immunoregulatory cancer-associated fibroblasts (iCAF). ConclusionThis study contributes to explain the lesser efficiency of PD-1/PD-L1-based ICIs in HR+/HER2-ILCs by comparison with HR+/HER2- IDCs, by shedding light on a complex ecosystem where tumor cells shape a distinctive stroma that contribute to prevent anti-tumor immune response activation. Altogether, our findings further support the rationale for combining iCAF-targeting strategy with an ad hoc immunotherapy (such as an anti-VTCN1/B7-H4 antibody-drug conjugates for example). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/728418v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1dfbc7eorg.highwire.dtl.DTLVardef@1d030a7org.highwire.dtl.DTLVardef@12a3e84org.highwire.dtl.DTLVardef@6e6139_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIImmune cells infiltrate both HR+/HER2- IDC and HR+/HER2- ILC tumors, but current ICIs are less effective in HR+/HER2- ILCs than HR+/HER2- IDCs. C_LI WHAT THIS STUDY ADDSO_LIThe anti-tumor immune response is mobilized but not effective in HR+/HER2- ILCs. C_LIO_LIA complex ecosystem - composed of immunoregulatory cancer-associated fibroblasts, high levels of TGFa, prostaglandin, acidosis, and a lack of antigen-presenting cells - prevents anti-tumor CD8+ cytotoxic T cell activation in HR+/HER2- ILCs. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYO_LITargeting the PD-1/PD-L1 axis is not the appropriate therapeutic strategy for HR+/HER2- ILCs. A more complex approach should be considered, notably those combining other immune-based strategies and iCAF targeting, which may offer a better chance to eradicate HR+/HER2- ILC tumor cells. C_LI

cancer biology↗

bioRxiv2025

Multi-omic analysis of colorectal adenocarcinoma identifies a new subtype of myofibroblastic cancer-associated fibroblast expressing high level of B7-H3 and with poor prognosis value.

The high mortality rate of colorectal cancer (CRC) combined with the lack of non-toxic and efficient personalized treatments makes it urgent to develop new targeted therapies for this disease. B7-H3 appears to be a good target as it is overexpressed in tumor tissue compared to normal tissue. However, B7-H3 is a molecule with ambivalent functions and is expressed by different cell types. This complexity contributed to the delay in identifying cell subtypes that express B7-H3 and their potential role in colorectal oncogenesis. In this study, we used in silico bulk, single-cell, and spatial transcriptomic data to investigate the clinical and biological characteristics of tumors with high B7-H3 expression, the precise nature of cells expressing high level of B7-H3, and their temporal appearance during colorectal oncogenesis. We found that tumors with high B7-H3 expression corresponded to tumors with a predominant stroma composed mainly of fibroblasts. Among them, two subtypes of ecm-myCAF fibroblasts and pro-fibrotic pericytes specifically expressed high levels of B7-H3, the former being an independent factor for poor prognosis in CRC. Finally, by examining precancerous lesions, we report that fibroblast subtypes with high levels of B7-H3 appear early during oncogenesis, especially at the inflamed stage. We also shed light on the fact that anti-B7-H3 immunotherapies might therefore preferentially target cells from the microenvironment rather than the tumor cells. This is particularly important to understand the mode of action of the anti-B7-H3 antibody-drug conjugate, which is currently being tested in clinical trials in several solid tumors. HighlightsO_LIHigh level of B7-H3 expression is associated with poor prognosis in colorectal cancer C_LIO_LIB7-H3 is recurrently found expressed by two subtypes of cancer-associated fibroblasts (CAF): pro-fibrotic pericytes and ecm-myCAF C_LIO_LIB7-H3high ecm-myCAF subtype is an independent poor prognosis for survival C_LIO_LIB7-H3high ecm-myCAF is detectable in pre-cancerous inflamed colonic tissues C_LI

cancer biology↗

bioRxiv2024

Epigenenomic and transcriptomic characterization of NPM1-mutated CN-AML subtypes

Cytogenetic normal AML with NPM1 mutations forms a distinct AML entity, associated with an intermediate prognosis and a heterogeneous response to treatment. We previously described an epigenetic biomarker, defined by the level of H3K27me3 on 70kb of the HIST1 cluster in patient blast DNA. This epigenetic mark separates cytogenetically normal NPM1mut AML into two groups of patients differing in their survival rate following chemotherapy. To better characterize the influence of the biomarker on disease progression, we performed transcriptomic and histone mark profiling on patient blasts according to the level of H3K27me3 HIST1. Our integrated analysis revealed that the two groups of patients display differences in terms of transcriptomic, chromatin landscape and cell surface markers, which could explain the clinical difference. Our profiling revealed novel targets and therefore constitutes an (epi)transcriptomic resource for NPM1 AML. It also highlights the power of epigenetic profiling to dissect the heterogeneity of a single AML genetic entity.

genomics↗

bioRxiv2023

Absence of chromosome axis proteins recruitment prevents meiotic recombination chromosome-wide in the budding yeast Lachancea kluyveri

Meiotic recombination shows broad variations across species and along chromosomes, and is often suppressed at and around genomic regions determining sexual compatibility such as mating type loci in fungi. Here we show that the absence of Spo11-DSBs and meiotic recombination on Lakl0C-left, the chromosome arm containing the sex locus of the Lachancea kluyveri budding yeast, results from the absence of recruitment of the two chromosome axis proteins Red1 and Hop1, essential for proper Spo11-DSBs formation. Furthermore, cytological observation of spread pachytene meiotic chromosomes reveals that Lakl0C-left does not undergo synapsis. However, we show that the behavior of Lakl0C-left is independent of its particularly early replication timing and is not accompanied by any peculiar chromosome structure as detectable by Hi-C in this yet poorly studied yeast. Finally, we observed an accumulation of heterozygous mutations on Lakl0C-left and a sexual dimorphism of the haploid meiotic offspring, supporting a direct effect of this absence of meiotic recombination on L. kluyveri genome evolution and fitness. Because suppression of meiotic recombination on sex chromosomes is widely observed across eukaryotes, the novel mechanism for recombination suppression described here may apply to other species, with the potential to impact sex chromosome evolution.

genetics↗