Biology subjects

Vimeux, L.

Publications and source records attributed to Vimeux, L..

7 recordsLinked to original sources

bioRxiv2026

Safety profiling of CAR-T cells using an organotypic human tissue platform

CAR-T-cell-associated on-target off-tumor (OTOT) toxicity represents a major safety concern, as recognition of target antigens on healthy tissues can trigger severe and potentially life-threatening complications. Predicting OTOT toxicity remains a challenge because current preclinical models fail to capture the complexity of native human tissues. Here, we developed a human organotypic tissue platform that enables functional assessment of CAR-T-cell activity in intact human tissues across organ-specific and inflammatory contexts. Using a panel of clinically relevant CAR-T-cell products with known OTOT toxicities, we demonstrate that the platform faithfully recapitulates clinically observed tissue-specific toxicity profiles. CAR-T cells targeting EGFR, HER2, and mesothelin induced inflammatory and cytotoxic responses in healthy human lung tissue, whereas CD19 CAR-T cells remained inactive. We further show that OTOT toxicity cannot be reliably predicted from antigen abundance alone but instead results from the integration of multiple target-dependent determinants, including CAR affinity, inflammatory context, antigen accessibility, and effector-cell dose. The platform also enables quantitative assessment of inflammatory and cytotoxic responses and supports evaluation of pharmacological and CAR design-based strategies to mitigate toxicity. Together, this work establishes the first human organotypic platform for functional modeling of CAR-T-cell-associated OTOT toxicity, providing a clinically relevant framework for preclinical safety evaluation and the rational development of safer engineered cell therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/740527v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@12c8addorg.highwire.dtl.DTLVardef@150d392org.highwire.dtl.DTLVardef@17218f7org.highwire.dtl.DTLVardef@1c54078_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Monocytes promote intraepithelial infiltration of effector memory CD8+ T cells in regressing tumors

Despite the clinical success of cancer immunotherapies, the cellular interactions driving tumor regression remain incompletely understood. Here, we investigated the dynamic remodeling of the tumor immune microenvironment during regression of transplanted PyMT mammary tumors following STING agonist treatment. Using scRNA-seq of sorted CD8+ T cells and myeloid cells, combined with imaging approaches, we identified major changes in both lymphoid and myeloid compartments during tumor regression. Regressing tumors showed a transient accumulation of Ly6Chi monocyte populations associated with a decline in macrophage subsets, while effector and memory CD8+ T-cell populations increased at the expense of exhausted T cells. Interaction analyses predicted enhanced chemotactic and adhesion interactions between CXCL9+ Ly6Chi monocytes and effector CD8+ T cells. Consistently, dynamic imaging revealed increased CD8+ T-cell motility and infiltration into tumor cores following treatment. In particular, CXCR6+ effector CD8+ T cells transiently accumulated within tumor islets during regression before relocalizing to stromal regions. Together, these findings reveal a coordinated spatiotemporal remodeling of myeloid and CD8+ T-cell populations during immunotherapy-induced tumor regression and highlight cooperative interactions that may promote durable anti-tumor immunity.

immunology↗

bioRxiv2024

Mitochondrial metabolism sustains CD8+ T cellmigration for an efficient infiltration into solid tumors

The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a much minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cells intra-tumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

immunology↗

bioRxiv2021

Tissue-resident FOLR2+ macrophages associate with tumor-infiltrating CD8+ T cells and with increased survival of breast cancer patients.

Macrophage infiltration is a hallmark of solid cancers and overall macrophage infiltration is correlated with lower patient survival and resistance to therapy. However, tumor-associated macrophages are phenotypically and functionally heterogeneous. Specific tumor-associated macrophage subsets might be endowed with antagonistic role on cancer progression and on the development of anti-tumor immunity. For instance, monocyte-derived TREM2+ tumor-associated macrophages have pro-tumorigenic and immunosuppressive functions. Here, we identify a discrete population of FOLR2+ tumor-associated macrophages positively correlating with patient survival in breast cancer. FOLR2+ macrophages are evolutionarily conserved across species and populate human and murine healthy mammary gland. Moreover, FOLR2+ macrophages co-localize with lymphoid aggregates containing CD8+ T cells in breast cancer and across ten other types of cancers. This study highlights antagonistic roles for tumor-associated macrophage subsets and paves the way for subset-specific therapeutic interventions in macrophages-based cancer therapies.

immunology↗

bioRxiv2020

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown remarkable clinical efficacy against advanced B cell malignancies but not yet against solid tumors. Here, we used fluorescent imaging microscopy and ex vivo assays to compare the early functional responses (migration, Ca2+ and cytotoxicity) of CD20 and EGFR CAR T cells upon contact with malignant B and carcinoma cells. Our results indicate that CD20 CAR T cells rapidly form productive ICAM-1-dependent conjugates with their targets. By comparison, EGFR CAR T cells only interact at first with a subset of carcinoma cells located at the periphery of tumor islets. After this initial peripheral activation, EGFR CAR T cells progressively infiltrate the center of tumor cell regions. The analysis of this two-step entry process shows that activated CAR T cells trigger the upregulation of ICAM-1 on tumor cells in an IFN{gamma}-dependent pathway. The blockade of ICAM-1/LFA-1 interactions prevents CAR T cell recruitment into tumor islets. The requirement for IFN{gamma} and ICAM-1 to enable CAR T cell entry into tumor islets is of significance for improving CAR T strategy in solid tumors.

immunology↗

bioRxiv2018

Blockade of β-adrenergic receptor signaling improves cancer vaccine efficacy through its effect on naive CD8+ T-cell priming

{beta}-adrenergic receptor ({beta}-AR) signaling, by acting directly on tumor cells and angiogenesis, has been showed to exert pro-tumoral effects. Growing evidence also suggests that {beta}-AR expressed by immune cells affect the associated anti-tumor immune response. However, how and where {beta}-AR signaling impinges the anti-tumor immune response is still unclear. Using a mouse model of vaccine-based immunotherapy, we show here that propranolol, a non-selective {beta}-blocker, strongly improved the efficacy of the vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TILs). However, propranolol had no obvious effect on the reactivity of CD8+ TILs, a result further strengthened by ex-vivo experiments showing that these cells are insensitive to AR signaling triggered by adrenaline or noradrenaline. In contrast, we show that naive CD8+ T cell activation was strongly inhibited by {beta}-AR signaling and that the beneficial effect of propranolol mainly occurred during their initial priming phase. We also demonstrate that the differential sensitivity of CD8+ TILs and naive CD8+ T cells is related to their activation status since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs, both exhibiting a down-regulation of the {beta}2-AR expression. These results reveal that the initial priming phase of the anti-tumor response in the tumor-draining lymph node is a decisive part of the suppressive effect of {beta}-AR signaling on the CD8+ T-cell response against cancer. These findings provide a rationale for the strategic use of clinically available {beta}-blockers in patients to improve cancer immunotherapies such as anti-cancer vaccination strategies.

immunology↗

bioRxiv2018

TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN/{beta} and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGF{beta}.

cancer biology↗