Biology subjects

Lantz, O.

Publications and source records attributed to Lantz, O..

11 recordsLinked to original sources

bioRxiv2026

Oncogenic fusions induce an extensive cancer-restricted cryptic proteome in Ewing sarcoma

How tumors generate a cryptic "dark" proteome absent from healthy tissues, and whether it can be reversibly activated, remains unclear. In Ewing sarcoma, all tumors are driven by EWSR1::ETS fusions, making it a tractable model to study dark proteome activation. Integrating matched transcriptomes, translatomes and proteomes from 48 patient tumors with long-read RNA sequencing, single-cell Ribo-seq, proteomics and immunopeptidomics in cell line models, we show that EWSR1::FLI1 acts as a reversible switch recurrently inducing hundreds of cancer-specific neoproteins. Many arise from canonical coding regions via intragenic transcription start sites, generating truncated or out-of-frame neoproteins. We uncover a fusion-dependent increase in ribosomal readthrough into poly(A) tails, generating a stable 80-amino-acid TRPM4 neoprotein that, despite lacking a stop codon, is the most abundant tumor-specific microprotein across patients. Proteomic, immunopeptidomic, and immunofluorescence analyses validate neoproteins as tumor-restricted antigens, revealing a therapeutically actionable cancer dark proteome controlled by one oncogenic fusion.

cancer biology↗

bioRxiv2026

Specific killing of Ewing sarcoma by TCR-T cells targeting public neogene-encoded antigens

EWSR1::FLI1, the oncogenic chimeric transcription factor driving Ewing sarcoma (EwS)induces expression of exquisitely EwS-specific neogenes (Ew_NGs) through neomorphic binding and transcription activation at GGAA microsatellites in genomic regions that are silent in normal tissues. We show that peptides encoded by Ew_NGs are presented on HLA-I complexes on EwS cells. The cytokine secretion of CD8+ T cells specific for Ew_NG-encoded HLA-I-bound peptides is activated by all HLA-I-matched EwS cells but not by non-EwS cells. These T cells kill EwS cells in an HLA-I restricted manner. This cytotoxicity is dependent on the expression of EWSR1::FLI1 and of the corresponding Ew_NG. It can be reproduced by transduction of the TCR into donor T cells (TCR-T) which kill EwS cells in vivo. Moreover, we show that neither off target nor allogeneic activation are observed with TCR-T thus paving the way for cell therapy in relapsed/resistant EwS patients for which therapeutic options are very limited. Statement of significanceThe chimeric transcription factor EWSR1::FLI1 generates tumor-specific neogenes encoding neoantigen presented by the HLA-I molecules of Ewing cells. Neoantigen-specific CD8+ T-cell clones and engineered TCR-T cells can selectively recognize and kill EwS tumor cells in vitro and in vivo.

immunology↗

bioRxiv2026

Mucosal-Associated Invariant T Cells Promote Atherosclerosis Through Monocyte-Driven Inflammation

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes that may contribute to inflammatory responses, although their specific role in atherosclerosis remains poorly understood. In this study, we identified MAIT cells within human atherosclerotic plaques and found that they were significantly enriched among CD3 T cells in plaques compared to matched peripheral blood samples. MAIT cells within plaques exhibited an activated phenotype and showed upregulation of genes associated with inflammation and cellular activation, compared to circulating MAIT cells from the same patients. Using murine models, we found that low-density lipoprotein receptor (Ldlr)-/- mice carrying the CAST locus, which confers naturally higher frequencies of MAIT cells, displayed increased MAIT cell accumulation in both the liver and atherosclerotic plaques when fed a high-cholesterol diet. In contrast, MAIT cell-deficient Ldlr-/-CAST MR1-/- mice exhibited a reduced atherosclerotic burden, diminished liver fibrosis, smaller myocardial infarcts following coronary artery ligation, without significant changes in plasma cholesterol levels. These atheroprotective effects were accompanied by lower monocyte counts in the bone marrow and blood, as well as reduced plaque macrophage accumulation in the plaques. Furthermore, deletion of CCR2, which impairs monocyte mobilization, abrogated the pro-atherogenic effects of MAIT cells, indicating that MAIT-driven atherogenesis occurs through a monocyte-dependent mechanism. Taken together, these findings identify MAIT cells as active contributors to vascular inflammation and position them as potential therapeutic targets for atherosclerosis and its complications.

immunology↗

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

Common origin for effector and regulatory Follicular and Tissue-Adapted CD4+ T cells in Non-Small Cell Lung Cancer

Tumor-invaded lymph nodes (LNs) serve as critical hubs for anti-tumor immunity, yet their role in orchestrating immune responses remains poorly understood. Using integrated single-cell RNA sequencing, T cell receptor sequencing, and chromatin accessibility profiling, we analyzed CD4+ T cells from matched blood, tumor-invaded LNs, and tumors of treatment-naive non-small cell lung cancer patients. We identified distinct immunological landscapes across these compartments. Compared to blood, tumor-invaded LNs and tumors were enriched for follicular regulatory T cells (Treg-Tfr), conventional T cell subsets with Tfh-like characteristics (Tconv-Tfh and Tconv-CXCL13), and tissue-resident memory Tregs (Treg-Trm). These populations share a BATF-dependent transcriptional program that governs T-cell activation and tissue adaptation, while simultaneously engaging distinct, subset-specific regulatory networks. Integrative TCR-RNA analysis revealed that tumor-reactive, neoantigen-specific T cell clones were enriched within these subsets and demonstrated extensive LN-tumor clonal sharing, indicating active recirculation between compartments. Through clonal coupling analysis and trajectory inference, we uncovered that Treg-Tfr cells function as multipotent progenitors that bifurcate into tissue-resident Treg-Trm or into ex-Tregs adopting a Tfh-like CXCL13+ ewector phenotype. Remarkably, follicular CD4+ T subsets from LNs and tumor were transcriptionally and epigenetically similar and localized to analogous germinal center niches. These findings establish tumor-invaded LNs as functional extensions of the tumor microenvironment that generate and maintain tumor-reactive CD4+ lineages. The identification of tissue-resident Treg-Tfr plasticity reveals a critical developmental checkpoint that could be therapeutically targeted to redirect immunosuppressive programs toward anti-tumor ewector responses.

immunology↗

bioRxiv2025

MAIT cells protect in severe pneumococcal pneumonia by regulating neutrophil/macrophage antimicrobial activities

Mucosal-Associated Invariant T (MAIT) cells populate the lung tissue where they contribute to defense against respiratory infections. While MAIT cells have been implicated in host resistance to infections caused by Gram-negative bacteria, their contribution in immunity against Gram-positive bacteria-driven pneumonia is still enigmatic. Here, we demonstrate that both mouse and human MAIT cells are activated during severe infection caused by Streptococcus pneumoniae, the major cause of community-acquired bacterial pneumonia. Upon infection, lung MAIT cells undergo a transcriptional reprogramming associated with acquisition of potent antimicrobial properties. MAIT cell-deficient mice are more susceptible to pneumococcal pneumonia, including higher mortality, uncontrolled bacterial growth and dissemination, and impaired neutrophil and interstitial macrophage activity. Moreover, prophylactic stimulation of MAIT cells using cognate antigen protects from pneumococcus-induced lethal pneumonia. These findings demonstrate that MAIT cells are key cellular actors during Gram-positive bacterial infections.

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↗

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↗

bioRxiv2019

PDL1 AND ICOSL DISCRIMINATE HUMAN SECRETORY AND HELPER DENDRITIC CELLS

Dendritic cells (DC) are described as immature at the steady state, with a high antigen capture capacity, turning into a mature state with a strong T cell stimulatory capacity upon activation. Using 16 different stimuli in vitro (130 observations), we describe two states of human activated dendritic cells. PDL1highICOSLlow \"secretory DC\" produced large amounts of inflammatory cytokines and chemokines but induced very low levels of T helper (Th) cytokines following DC-T co-culture; conversely PDL1lowICOSLhigh \"helper DC\" produced low levels of secreted factors but induced high levels of Th cytokines characteristic of a broad range of Th subsets. Secretory DC were phenotypically identified in T cell inflamed primary head and neck squamous cell carcinoma. RNAseq analysis showed that they expressed a typical secretory DC signature, including CD40, PVR, IL1B, TNF, and CCL19. This novel and universal functional dichotomy of human DC opens broad perspectives for the characterization of inflammatory diseases, and for immunotherapy.

immunology↗

bioRxiv2019

A Comprehensive Assessment of Demographic, Environmental and Host Genetic Associations with Gut Microbiome Diversity in Healthy Individuals

BackgroundThe gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Interieur Consortium, a total of 1,000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20 - 69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. ResultsAmong 110 demographic, clinical and environmental factors, 11 were identified as significantly correlated with -diversity, {beta}-diversity or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between >5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. ConclusionIn a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals.

genomics↗