Biology subjects

Denanglaire, S.

Publications and source records attributed to Denanglaire, S..

4 recordsLinked to original sources

bioRxiv2026

TCR Signal Strength and Eomes Coordinate CD8⁺ T Cell Fate and Antitumor Immunity in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) poses a persistent barrier to effective immunotherapy, in part due to the emergence of exhausted CD8+ T cells. Using a hydrodynamic, autochthonous HCC model based on Sleeping Beauty-mediated delivery of oncogenic drivers and defined OVA-derived antigens, we could manipulate antigen affinity under physiological priming conditions. With this system, we examined how TCR signal strength and the transcription factor Eomesodermin (Eomes) shape CD8+ T cell fate in vivo. High-affinity stimulation supported robust effector differentiation and the formation of tissue-resident memory T cells (Trm), resulting in early tumor control. In contrast, low-affinity stimulation induced elevated Eomes expression and favored rapid transition toward an exhausted (Tex) phenotype. Genetic repression of Eomes enhanced Trm differentiation in high-affinity CD8+ T cells and delayed tumor relapse, whereas ectopic Eomes expression accelerated exhaustion and led to earlier tumor recurrence. Under low-affinity conditions, Eomes deficiency increased the Trm-to-Tex ratio but remained insufficient to restore effective antitumor immunity, indicating that weak TCR engagement imposes constraints that cannot be overcome by Eomes loss alone. These findings reveal that the strength of TCR engagement shapes CD8+ T cell fate in HCC, while Eomes selectively biases this process toward exhaustion at the expense of effector and resident memory programs, ultimately influencing the durability of tumor control. SynopsisThis study reveals that the strength of T-cell receptor signaling fundamentally steers whether CD8+ T cells in liver cancer become durable tumor-fighting cells or slip into exhaustion, pinpointing Eomes as a key factor that pushes cells toward dysfunction. By uncovering how antigen affinity and Eomes jointly shape antitumor immunity, the work offers new conceptual and therapeutic avenues for improving the persistence and effectiveness of immunotherapies in hepatocellular carcinoma.

immunology↗

bioRxiv2024

Interferon-γ driven differentiation of monocytes into PD-L1+ and MHC II+ macrophages and the frequency of Tim-3+ tumor-reactive CD8+ T cells within the tumor microenvironment predict a positive response to anti-PD-1-based therapy in tumor-bearing mice

While immune checkpoint inhibitors have demonstrated durable responses in various cancer types, a significant proportion of patients do not exhibit favourable responses to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we established a bilateral tumor model using P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds favourably to anti-PD-1 treatment, thus providing a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade (ICB)-based immunotherapies. Moreover, this model allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. Here, we demonstrated that tumor-reactive CD8+ T cell clones expressing high levels of Tim-3 were associated to a positive anti-tumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and non-responding mice. An IFN{gamma}-enriched TME appeared to promote the differentiation of monocytes into PD-L1pos MHC IIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of non-responding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte to macrophage route may hamper the response to ICB. These insights will direct future research towards a temporal analysis of TAMs, aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may potentially pave the way to novel strategies to enhance the efficacy of PD-1 blockade.

immunology↗

bioRxiv2020

Long-term homeostatic T cell proliferation is driven by AMPK-dependent regulation of oxygen reactive species

The AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial.Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector / memory T cell survival. In particular, AMPK promoted accumulation of effector / memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells.Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2019

Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells

ROR{gamma}t-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of ROR{gamma}t expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of ROR{gamma}t+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that ROR{gamma}t+ Treg development is controlled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-{beta}-derived signals act in favor of ROR{gamma}t+ Treg development. Ectopic expression of c-Maf did not rescue ROR{gamma}t expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-{gamma}/STAT1 signaling pathway acts as a negative regulator of ROR{gamma}t+ Treg differentiation in a c-Maf independent fashion.\n\nThese data thus argue for a complex integrative signaling network that finely tunes ROR{gamma}t expression in Tregs. The finding that type 1 inflammation impedes ROR{gamma}t+ Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.

immunology↗