Biology subjects

Amigorena, S.

Publications and source records attributed to Amigorena, S..

10 recordsLinked to original sources

bioRxiv2025

Analysis of intratumoral immune heterogeneity reveals spatial organisation of immunosuppression in breast cancer

Recent advances in single-cell transcriptomics have illuminated intratumoral heterogeneity (ITH) in breast cancer, yet the spatial organization and functional states of immune populations within luminal tumors remain poorly understood. Here, we generated a spatially and clonally resolved single-cell immune atlas of early-stage luminal breast cancer by integrating paired single-cell RNA/TCR sequencing with multiplex immunohistochemistry across three spatially distinct tumor regions: central (core-proximal), intermediate and peripheral (invasive margin-proximal), in five patients. Peripheral regions are enriched in naive CD4 T cells, monocytes, dendritic cells, and memory CD8 T cells with bystander properties, alongside TCF1+ exhausted progenitors (Tpex), and displayed elevated antigen presentation and tertiary lymphoid structures (TLS) signatures. In contrast, central regions harbor macrophages, clonally expanded regulatory T cells (Tregs), and two subsets of terminally exhausted CD8 T cells (Tex), one tissue-resident and one circulating, both expressing tumor-reactive features. Clonal overlap was observed between peripheral Tpex and central, tissue-resident Tex cells, revealing a spatially confined differentiation trajectory toward exhaustion within the tumor microenvironment. Central T cells also upregulate TGF-{beta} signaling and metabolic pathways including fatty acid oxidation and oxidative phosphorylation, consistent with adaptation to an immunosuppressive microenvironment. Together, these findings reveal a spatially structured immune landscape in luminal breast cancer, marked by progressive immunosuppression from the tumor margin to the core, providing a framework for future region-specific immunotherapeutic strategies.

immunology↗

bioRxiv2025

Transposon invasion of primate genomes shaped human inflammatory enhancers and susceptibility to inflammatory diseases

Human immune inflammatory response reflects the evolutionary adaptation of immune-cell regulatory elements1, where recent mutations can control both pathogen defence and susceptibility to chronic inflammatory and autoimmune diseases2-4. The impact of the deeper evolutionary history of these elements within primate genomes on human inflammatory responses remains poorly understood. Evolutionary young transposons have uniquely reshaped primate genomes5 and spread novel cis-regulatory sequences6. To understand how these events influenced human inflammation, we traced sequence changes in annotated human immune-cell enhancers back to macaque. We show that Alu elements and endogenous retroviruses dispersed motifs for the inflammation-related NF-{kappa}B and IRF1, redefining their binding patterns and contributing most prominently to great ape-specific binding sites. After the human-macaque split, many of these motifs shifted toward higher predicted binding affinity. In humans, population genetics analyses reveal that positive selection favors alleles, often Alu-derived, that increase enhancer affinity toward NF-{kappa}B. Enhancers containing Alu elements are more likely to undergo positive selection at the locus level, particularly when associated with chronic inflammatory diseases. As the most mutable enhancer sequences, Alus harbor disproportionately high numbers of single nucleotide polymorphisms and significantly contribute to selected alleles, some associated with chronic inflammatory diseases. We propose that the invasion of primate-specific transposons has created unique opportunities to adapt inflammatory responses in rapidly evolving great apes, with ancestral Alus continuing to influence evolutionary potential in humans.

genomics↗

bioRxiv2024

The DivisionCounter, a method for counting large ranges of cell divisions in vivo, reveals cell dynamics of leukemic cell killing via CAR-T therapy

Cell division drives multicellular growth and its dysregulation can cause disease. While approximately 44 divisions are needed to produce without death all 1013 cells in the human body, current methods are limited to count 10 cell divisions in vivo across diverse mammalian cell types. Here we introduce the DivisionCounter, a method to count cell division in vivo over large division ranges ([~]70 divisions) using an easy fluorescence readout. We demonstrate that the DivisionCounter accurately measures the average cell division count of cells both in vitro and in vivo. Its use revealed that leukemia tumor division rates are independent of the organs specific microenvironment and CAR-T cell treatment, providing an estimate of tumor death rates in vivo. The DivisionCounter method holds unique potential for quantifying contributions of cell division, death, and migration to the growth of healthy and pathological mammalian tissues.

immunology↗

bioRxiv2024

Epigenetic control of CD8+ T cell tissue homing and tissue resident memory T cell precursors by the histone methyltransferase SUV39H1

Activation of CD8+ T cells leads to the differentiation of short-lived terminal effectors and memory precursors. Some of these memory precursors remain in lymphoid organs and become long-lived central memory T cells (TCM), while others home to non-lymphoid peripheral tissues early after antigen recognition and differentiate into tissue resident memory T cells (TRM). The early stages of memory precursor tissue homing and TRM differentiation remain poorly understood. We show here that at steady state, during space-induced "homeostatic" expansion, and after flu infection, deletion of the histone 3-lysine 9 methyltransferase SUV39H1 in CD8+ T cells, increases the homing to non-lymphoid tissues (including liver, lungs, gut and skin). SUV39H1-defective cells in tissues express CD49d and differentiate into CD69+/CD103-TRM after adoptive transfer or Flu infection. SUV39H1-defective T cells that accumulate in lungs are fully functional in both Flu re-infection and lung tumor models. We conclude that SUV39H1 restrains CD8+ T cell tissue homing and TRM differentiation in WT mice. These results should encourage the use of SUV39H1-depletion in the context of adoptive T cell therapies to enhance tissue homing, thereby optimizing the efficiency of target cell eradication and long-term protection in the context of infection and cancer.

immunology↗

bioRxiv2022

Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

immunology↗

bioRxiv2021

Induction of transposable element expression is central to innate sensing

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

immunology↗

bioRxiv2021

In vivo genome-wide CRISPR screens identify SOCS1 as a major intrinsic checkpoint of CD4+ Th1 cell response

The expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using in vivo genome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-{gamma} signals and blocking multiple signaling pathways to abrogate CD4+ Th1 cell response. In CD8+ T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+ T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+ T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.

immunology↗

bioRxiv2020

Contribution of resident and circulating precursors to tumor-infiltrating CD8+ T cell populations in non-small cell lung cancer patients

Tumor-infiltrating lymphocytes (TILs) in general, and CD8+ TILs in particular, represent a favorable prognostic factor in non-small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations, however, remain poorly understood. Using a combination of single cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8+ TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxta-tumor tissue (tissue resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, filiation and functional organization in primary NSCLC.

immunology↗

bioRxiv2020

Small molecule enhancers of endosome-to-cytosol import augment anti-tumour immunity

Efficient cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumour immune responses. Yet, several steps of antigen intracellular traffic during cross-presentation are incompletely understood: in particular, the molecular mechanisms and the relative importance of antigen import from endocytic compartments into the cytosol. Here, we asked whether antigen import into the cytosol is rate-limiting for cross-presentation and anti-tumour immunity. By screening 700 FDA-approved drugs, we identified 37 import enhancers. We focused on prazosin and tamoxifen, and generated proteomic organellar maps of drug-treated DCs, covering the subcellular localisations of over 2000 proteins. By combining organellar mapping, quantitative proteomics, microscopy, and bioinformatics, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release into the cytosol. Enhancing antigen import facilitates cross-presentation of both soluble and cell-associated antigens. Systemic administration of prazosin also led to reduced growth of MC38 tumours and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumour immune responses and efficacy of checkpoint blockers. HighlightsO_LIQuinazolamine derivatives are potent enhancers of antigen import into the cytosol C_LIO_LIAntigen import enhancement occurs as a consequence of lysosomal trapping C_LIO_LIAntigen import enhancers facilitate cross-presentation and synergise with PD-L1 C_LIO_LIProteomic organellar maps of cDC1s as a tool to detect biological effects of drugs C_LI O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/079491v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d55245org.highwire.dtl.DTLVardef@c3d43org.highwire.dtl.DTLVardef@189fbc8org.highwire.dtl.DTLVardef@1f1280e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Surface LSP1 is a phenotypic marker distinguishing human classical versus monocyte-derived dendritic cells

Human mononuclear phagocytes comprise several subsets of dendritic cells (DCs), monocytes and macrophages. Distinguishing one population from another is challenging, especially in inflammed tissues, due to the promiscuous expression of phenotypic markers. Using a synthetic library of humanized llama single domain antibodies, we identified a novel surface marker for human naturally-occuring monocyte-derived DCs. Our antibody targets an extra-cellular domain of LSP-1, specifically on monocyte-derived DCs, but not on monocytes, macrophages or classical DCs. Using this antibody, we provide evidence that the recently described blood DC3 population does not correspond to circulating monocyte-derived DCs. Our findings will pave the way for a better characterization of human mononuclear phagocytes in pathological settings.

immunology↗