Biology subjects

Mestrallet, G.

Publications and source records attributed to Mestrallet, G..

5 recordsLinked to original sources

bioRxiv2025

Targeting neoantigens conserved across organs and species overcomes tumor immune escape

Neoantigen-targeted immunotherapies hold promise for cancer treatment, but current personalized approaches are time-consuming and costly. Here, we identify neoantigens encoded by Ptprs and Igf2r that are shared across murine mismatch repair-deficient colorectal and breast tumors and unexpectedly conserved in human colorectal, endometrial, gastric, and prostate cancers. These neoantigens elicit spontaneous, organ-spanning CD8+ T cell-mediated memory responses that are enhanced by immune checkpoint blockade. Vaccination with mRNA/lipid nanoparticles encoding these conserved neoantigens suppresses tumor growth across prophylactic and therapeutic models, including checkpoint-resistant orthotopic tumors. Tumor rejection is accompanied by antigen spreading, abscopal effects, and infiltration by clonally diverse T cells, dendritic cells, and MHC I/II+ macrophages producing CXCL9/10, CCL5/8, and TNF. Tumor cells also show activation of innate and adaptive pathways, including MHC and ISGs overexpression. Our results uncover a conserved anti-tumor immune mechanism and support the development of off-the-shelf neoantigen vaccines across tissues and species.

immunology↗

bioRxiv2025

Epigenetic profile drives accurate survival prediction in breast cancer via a multi-omics machine learning model

Accurate overall survival (OS) prediction is key for personalized treatment in breast cancer, but mutation burden alone is insufficient. To improve prognostic accuracy, we integrated genomic, transcriptomic, proteomic, epigenetic, and clinical features from 802 breast cancer patients to develop BANDOL (Breast cancer Analysis with Neoplastic Data and Omics Learning), a Random Survival Forest model. BANDOL correctly predicted survival ranking in 73% of patient pairs and outperformed mutation-based models (time-dependent AUC: 0.9-1 vs. 0.4-0.9). Immune activation signatures correlated with a longer OS after therapy, while a shorter OS was linked to TREM2 myeloid cells, B cells, and leptin signaling. The transferability of the model was further explored in three independent TCGA cohorts from distinct cancer types (uterine, ovarian and lower-grade glioma), where moderate predictive performance was maintained despite biological differences between tumors. Epigenetic features were the strongest OS predictors for BANDOL. Current therapies may be combined with strategies to target the methylations of ME3, PPARG, OLIG3 and SLC25A22 genes. This study demonstrates that multi-omics integration via machine learning enhances survival prediction and reveals actionable biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/667894v6_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1f3efc6org.highwire.dtl.DTLVardef@2cff0org.highwire.dtl.DTLVardef@a1c3baorg.highwire.dtl.DTLVardef@392114_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Coordinated macrophage and T cell interactions mediate response to checkpoint blockade in colorectal cancer.

Mismatch repair deficiency (MMRd), either due to inherited or somatic mutation, is prevalent in colorectal cancer (CRC) and other cancers. While anti-PD-1 therapy is utilized in both local and advanced disease, up to 50% of MMRd CRC fail to respond. Using animal and human models of MMRd, we determined that interactions between MHC+ C1Q+ CXCL9+ macrophages and TCF+ BHLHE40+ PRF1+ T cell subsets are associated with control of MMRd tumor growth, during anti-PD-1 treatment. In contrast, resistance is associated with upregulation of TIM3, LAG3, TIGIT, and PD-1 expression on T cells, and infiltration of the tumor with immunosuppressive TREM2+ macrophages and monocytes. By combining anti-PD-1 with anti-LAG3/CTLA4/TREM2, up to 100% tumor eradication was achieved in MMRd CRC and remarkably, in >70% in MMRp CRC. This study identifies key T cell and macrophage subsets mediating the efficacy of immunotherapy in overcoming immune escape in both MMRd and MMRp CRC settings. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/637954v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1778bd6org.highwire.dtl.DTLVardef@17da4e5org.highwire.dtl.DTLVardef@1d4d1d2org.highwire.dtl.DTLVardef@11b58e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAnti-PD-1 therapy leads to the accumulation and colocalization of MHCI/II+ C1Q+ CXCL9+ macrophages and DCs with TCF+ CCL5+ T cells that have high TCR diversity. C_LIO_LIResistance to anti-PD-1 therapy involves multiple T cell checkpoints, TREM2+ macrophages, IL1B+ TREM1+ monocytes and neutrophils, and IFITM+ tumor cells. C_LIO_LISimultaneous blockade of PD-1, LAG3, CTLA-4 and TREM2 dramatically prevents progression of both MMRd and MMRp tumors. C_LIO_LICombination therapy completely eliminates tumors by leveraging MHC+ macrophage, CD4+ and CD8+ T cell interactions, facilitating durable anti-tumor effects. C_LI

immunology↗

bioRxiv2024

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoidstructures in cancer

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFN{gamma}-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

immunology↗

bioRxiv2023

Immune response and resistance of clear cell renal cell carcinoma patients following immune checkpoint blockade.

175,000 patients die because of renal cell carcinoma (RCC) each year. Clear cell renal cell carcinoma (ccRCC or KIRC) is the most frequent subtype of RCC. Current therapies include immune checkpoint inhibitors (ICB) or VEGFR tyrosine kinase inhibitors (TKIs). However, many patients did not respond to ICB and immune resistance still occurred. Immune resistance may be explained by expression of various immune checkpoints and immunosuppressive pathways in KIRC patients. Thus, it is important to identify mechanisms driving immune response and resistance following ICB. To address this question, we performed an analysis of 3 KIRC cohorts treated with 3 different ICB. Overall, 20-30% of KIRC patients respond to ICB. Responders with metastasized stage IV cancer with tumorectomy prior to anti-PD-L1 are characterized by an increase in CD4+ and CD8+ T cell infiltration, and by better antigen presentation and T cell responses (BTN3A1, PRF1 and CD27 genes). However, the expression of CTLA4, TIGIT and BTLA in Th1, Th17 and M2 subsets may limit complete response in responders. Importantly, non-responders patients are characterized by higher infiltration by macrophages, and by overexpression of regulatory gene (ADORA2A) in Th2, CD8+ T cell, M1 and M2 clusters. Targeting these pathways may help to develop combination therapies to improve KIRC patient outcomes.

immunology↗