Biology subjects

Lacourrege, M.

Publications and source records attributed to Lacourrege, M..

3 recordsLinked to original sources

bioRxiv2024

HERV-derived epitopes represent new targets for T-cell based immunotherapies in ovarian cancer

BackgroundOvarian cancer represents the most lethal gynecological cancer with poor results of checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T cell epitopes for cancer immunotherapy regardless of the tumor mutational burden. MethodsA transcriptomic analysis based on RNA-sequencing (RNA-seq) was developed to quantify the expression of HERV-K sequences containing the selected epitopes. The presence of HERV-K/HML-2 Gag antigen was then assessed by immunohistochemistry (IHC) on tumor microarrays from ovarian cancer samples and normal ovarian tissues. A specific immunopeptidomics approach was developed to detect epitopes on HLA molecules. Epitope-specific CD8+ T cells were quantified by multimer staining and in vitro target cell killing was evaluated using xCELLigence technology. In vivo antitumor efficacy of HERV-specific T cells was assessed in an avian embryo model. ResultsEpitope-containing HERV transcripts were significantly higher in ovarian cancers compared to normal tissues. The presence of HERV-K/HML-2 Gag antigen was confirmed by IHC in 20/40 (50%) ovarian cancers while no Gag expression was found in normal ovarian tissue samples. Immunopeptidomics analysis showed the presence of epitopes on HLA molecules on the surface of ovarian tumor cell lines but not on normal primary cells from critical tissues. HERV-specific T cells were detected among tumor infiltrating lymphocytes (TILs) from ovarian cancers, confirming the immunogenicity of these epitopes in patients. In vitro, HERV-specific T cells specifically killed ovarian cancer cells in an HLA class I-restricted manner while sparing normal HLA-A2-positive primary cells derived from critical tissues. Epitope-specific CD8+ T cells exhibited a strong anti-tumoral activity in vivo, inducing a highly significant decrease in tumor volume in comparison with control groups. ConclusionThese results provide the preclinical rationale for developing T-cell based approaches against HERV-K-derived epitopes in ovarian cancer. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/603392v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1c889b8org.highwire.dtl.DTLVardef@c9b0c5org.highwire.dtl.DTLVardef@1748100org.highwire.dtl.DTLVardef@1c129cc_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LISome HERVs are specifically overexpressed in ovarian cancer compared to normal tissues. C_LIO_LIHERV-K/HML-2 Gag antigen is detected by immunohistochemistry in ovarian cancers but not in normal ovarian tissues. Furthermore, HERV-K-derived epitopes are presented on HLA molecules on the surface of ovarian cancer cells but not on normal cells. C_LIO_LIThese epitopes are immunogenic in patients and induce high-avidity CD8+ T cells that specifically kill ovarian cancer cells in vitro and in vivo while sparing normal cells. C_LI

immunology↗

bioRxiv2023

Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos

BackgroundFollicular lymphoma (FL) is an incurable B-cell malignancy that constitutes a quarter of all lymphomas. Although RCHOP immuno-chemotherapy induces high rates of complete remission, almost all FL patients experience multiple relapses post-treatment. The limited understanding of treatment response heterogeneity is due to the absence of in vitro or in vivo experimental models, primarily because tumor cells heavily rely on their microenvironment to survive. In this study, we present an innovative xenograft model of primary FL cells in avian embryos, circumventing these limitations. MethodsWe developed the FL-AVI-PDX model by transplanting 20 biopsy FL samples, including good (n=11) and poor clinical responders (POD24, n=9), into chicken embryos. Each set of embryos was treated with RCHOP or vehicle intravenously. We evaluated the effect of immuno-chemotherapy on tumor volume by light sheet microscopy and on tumor biology by transcriptomic analysis at the single-cell level. ResultsWe successfully engrafted all samples in avian embryos. We found that RCHOP treatment in ovo led to tumor volume reduction, which predicted progression-free survival in multivariate analysis, demonstrating the models capacity to capture clinical heterogeneity at the patient level. The FL-AVI-PDX model also provided a unique opportunity to analyze the transcriptomic impact of RCHOP on FL cells using single-cell RNA sequencing. We identified a signature of 21 genes upregulated after RCHOP exposure, displaying significant intra-tumoral heterogeneity. As a proof of concept, we validated the functional involvement of BAX, a gene from the RCHOP-induced signature, as a critical effector of immuno- chemotherapy in vitro and in avian embryos. ConclusionsThe FL-AVI-PDX model is a platform for functional precision oncology in primary FL cells that captures both inter- and intra-patient heterogeneity of clinical response to a complex therapeutic regimen. It offers a unique opportunity to better understand FL biology, opening perspectives for the development of new drugs.

cancer biology↗

bioRxiv2022

An in vivo avian model of human melanoma to perform rapid and robust preclinical studies

Metastatic melanoma patients carrying a BRAFV600 mutation can be treated with BRAF inhibitors (BRAFi), in combination with MEK inhibitors (MEKi), but innate and acquired resistance invariably occurs. Resistance can involve transcriptional- and epigenetic-based phenotypic adaptations, as yet unpredictable. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDX). In this in vivo paradigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi targeted therapies can be reliably modeled in these AVI-PDX, as well as synergies with other drugs, such as HDACi. We further provide proof-of-concept that the AVI-PDX models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.

cancer biology↗