Biology subjects

Goriely, S.

Publications and source records attributed to Goriely, S..

3 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↗

bioRxiv2021

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1 and HIF2) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2{Delta}Treg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-{gamma} in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2{Delta}Treg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-{gamma} production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2 (PHD2-HIF2{Delta}Treg mice), but not in PHD2-HIF1 (PHD2-HIF1{Delta}Treg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2 axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2 axis in regulatory T cell phenotype and in vivo function.

immunology↗