Biology subjects

Rousseau, B.

Publications and source records attributed to Rousseau, B..

6 recordsLinked to original sources

bioRxiv2026

Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB), although homologous recombination-deficient (HRD) tumors may derive benefit. In the POLAR trial of maintenance pembrolizumab plus olaparib after platinum-based chemotherapy for metastatic PC, responses remained heterogeneous. To define determinants of productive antitumor immunity, we integrated longitudinal blood TCR sequencing with tumor single-cell and spatial profiling. Durable benefit was associated with rare tumor-infiltrating, peripherally expanding (TIE) CD8+ T cell clonotypes, a subset of which were functionally neoantigen-reactive. TIE patients showed markedly prolonged survival beyond established genomic and immune biomarkers. Conversely, resistance was associated with spatial T cell exclusion, myCAF-rich stromal remodeling, basal-like/KRAS-associated malignant-cell programs, and expansion of CTLA4 regulatory T cells linked to local immunosuppressive remodeling. These findings define a clonotype-resolved framework for immune monitoring and identify complementary stromal, tumor-intrinsic, and regulatory immune barriers that may guide rational combination immunotherapy in PC.

cancer biology↗

bioRxiv2026

Extracellular DNASE1L3 dysfunction fuels obesity-driven inflammation and metabolic syndrome

Obesity, a global health crisis affecting 16% of the world population, is characterized by chronic inflammation that contributes to health complications such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging evidence suggests that self-DNA released from dying cells aberrantly activates inflammatory responses during obesity. However, the role of extracellular deoxyribonucleases (DNASEs), which at steady state regulate abundance of extracellular self-DNA, remains poorly understood in this context. Here, we show that individuals with obesity exhibit elevated levels of circulating cell-free DNA (cfDNA) with a distinctive end-motif signature, anti-DNASE1L3 autoantibodies and a reduction in circulating DNASE activity. These cfDNA alterations correlate with the severity of obesity and can be corrected by therapeutic intervention such as bariatric surgery. Similarly, mice fed a high-fat diet (HFD) displayed increased cfDNA levels and decreased DNASE activity. Genetic deficiency of the extracellular nuclease DNASE1L3 in mice worsened HFD-induced metabolic complications, including glucose intolerance, insulin resistance, MASLD, and metabolic tissue inflammation. Conversely, targeted supplementation of DNASE1L3 in the liver using adeno-associated viral vectors protected obese mice from developing MASLD and liver inflammation. These findings uncover a novel role of DNASE1L3 in controlling obesity-associated inflammation and its potential therapeutic use for preventing metabolic disease.

pathology↗

bioRxiv2026

POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer

Pancreatic cancer (PC) is broadly resistant to immune checkpoint blockade, although a subset of homologous recombination-deficient (HRD) tumors exhibits durable immune engagement. The genomic features that distinguish these immune-responsive tumors from immune-inert HRD tumors remain poorly understood. Here we identify a microhomology-mediated end joining (MMEJ) repair scar, the MMEJ Deletion Footprint (MDF), as a genomic readout of POLQ-associated error-prone repair that enriches for frameshift indels. Across the multi-omic discovery cohort integrating tumor genomics, single-nucleus transcriptomics and spatial immune profiling, MDF-high HRD PC exhibited increased frameshift-indel-derived neoantigens and interferon programs. MDF was further associated with remodeling of the myeloid compartment toward MHC II-high dendritic cell-like antigen-presenting macrophage states and the immune synapse architecture marked by increased spatial interaction between APC-like macrophages and cytotoxic CD8+ T cells. These tissue-level features aligned with a functional trajectory shift of CD8+ T cells, consistent with effective anti-tumor immunity and was associated with favorable clinical outcomes of patients. Together, our findings position MMEJ-linked repair scarring as actionable biology that connects an HRD genotype to immune organization and suggests rational immunotherapy combinations that may enhance antigen presentation and myeloid activation to extend durable benefit in HRD-lineage cancers.

cancer biology↗

bioRxiv2025

Discovery of a DNA-based Optical Nanotube Sensor for Glucose Using Clustering and Deep Learning Algorithms

Glucose sensing is vital for managing diabetes. However, current sensors are invasive and secrete enzymatic byproducts that are inflammatory and toxic. Though DNA-wrapped single-walled carbon nanotubes (DNA-SWCNTs) emit fluorescence that is ideal for enzyme-free optical sensing, existing approaches have yet to identify a DNA sequence that can elicit a fluorescence response to glucose. We develop an approach based on clustering to design a diverse library of 90 DNA sequences to screen for a glucose response. The most responsive sequence was further improved based on favorable mutations predicted by deep learning and pattern recognition. This combination of experimental screening and supervised and unsupervised machine learning represents a generalizable approach to developing DNA-SWCNT sensors for even the most elusive analytes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/652529v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@e01org.highwire.dtl.DTLVardef@1977c45org.highwire.dtl.DTLVardef@5fc0e2org.highwire.dtl.DTLVardef@70763f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection

The involvement of {gamma}{delta} TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. {gamma}{delta} T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of {beta} T cell deficient mice in order to analyze the memory potential of {gamma}{delta} T cells. As for CMV-specific {beta} T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ {gamma}{delta} TEM that principally localized in infected organ vasculature. Typifying T cell memory, {gamma}{delta} T cell expansion/proliferation in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection involved the T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR {delta} chain repertoire as evidenced by next generation sequencing. The {gamma}{delta} T cell secondary response to MCMV was composed by a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, Long-term-primed {gamma}{delta} TCM cells, but not {gamma}{delta} TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. Overall, our study uncovered memory properties of long-lived TCM {gamma}{delta} T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches. AUTHOR SUMMARYCytomegalovirus (CMV) is a widespread, latent virus that can cause severe organ disease in immune-compromised patients. Anti-CMV memory immune responses are essential to control viral reactivation and/or reinfection events that commonly take place in solid organ transplantation. The role of {gamma}{delta} T-cell receptor bearing lymphocytes could be crucial in this context where immunosuppressive/ablative treatments cause suboptimal and/or delayed {beta} T cell responses. Here we asked whether {gamma}{delta} T cells could compensate for the absence of {beta} T cells in the long-term control of mouse CMV infection. Three months post-primary viral challenge in {beta}-T cell deficient mice, {gamma}{delta} T cells displayed similar features as cytolytic, CMV-specific {beta} CD8 T cells. We showed that previous priming with CMV endowed {gamma}{delta} T cells with an enhanced antiviral potential and that long-term maintenance of {gamma}{delta}-mediated antiviral protection was dependent on {gamma}{delta} central memory T cells (TCM). The {gamma}{delta} T cell response to a secondary CMV challenge was dependent on {gamma}{delta} TCR-signaling and generated a private TCR {delta} repertoire as observed in human. Our results sustain the adaptive-like properties of these unconventional T cells and reveal the interest of targeting {gamma}{delta} TCM subset in novel antiviral vaccination approaches.

immunology↗

bioRxiv2019

Counteracting resistance to targeted therapy in melanoma by inhibiting discoidin domain receptors

Anti-BRAF plus anti-MEK are used as first-line treatment of patients with metastatic melanomas harboring BRAF V600E mutation. The main issue with targeted therapy is acquired cellular resistance. In 70% of acquired resistance, melanoma cells switch their phenotype and become more aggressive and invasive. The molecular signature of this phenotype is MITF low, AXL high associated with actin cytoskeleton reorganization. After this switch, resistant cells present an anarchic cell proliferation due to MAP kinase pathway hyper-activation. We demonstrate that resistant cell lines presenting phenotype switching overexpress DDR1 and DDR2. We show that DDR2 inhibition induces a decrease in AXL and reduces actin stress fiber formation. Once this phenotype switching is acquired, we report that both DDRs promotes tumor cell proliferation, but only DDR2 can over-activate the MAP kinase pathway in resistant invasive cells in vitro and in vivo. Therefore, DDRs inhibition could be a promising strategy for countering this resistance mechanism. SignificanceOur results show that DDR2 is a relevant target in melanoma resistance. DDR2 is required at the beginning of resistance for melanoma cell phenotype switching to occur. After phenotype switching, DDRs promote tumor cell proliferation of resistant invasive melanoma cells, but only DDR2 is able to over-activate the MAP kinase pathway. We put forward dasatinib (a DDR inhibitor) as a potential second-line treatment after targeted dual therapy for resistant patients overexpressing DDRs.

cancer biology↗