Biology subjects

Fuentealba, J.

Publications and source records attributed to Fuentealba, J..

6 recordsLinked to original sources

bioRxiv2026

Associations between multivariate profiles, lifestyle behaviors and reaction time performance in active young adults

Lifestyle behaviors influence cardiometabolic and cognitive health through multiple interconnected processes, involving metabolic, cardiovascular, behavioral and cognitive factors. This study aimed to assess associations between multivariate plasma and physiological profiles, and behavioral parameters, and their potential association with reaction time (RT) in active young adults. Data on physical activity levels were collected from wearable devices and GPAQ questionnaire, along with anthropometric and clinical assessments, cognitive tests, and blood analyses. Principal component analysis was performed separately for physiological and plasma parameters, retaining the first two principal components (PCs) from each analysis. Multiple linear regression models were used to evaluate the associations between plasma, sex, physical activity levels (METs), daily step count, and alcohol/marijuana use on physiological PC1/PC2 scores, as well as RT. Continuous independent variables were previously categorized, and combined variables were created to represent specific combinations between plasma/physiological PC1 categories and sex. Physiological PC1 (blood pressure) was associated with combined plasma PC1 (insulin/HOMA-IR)-sex variable, total METs and alcohol consumption (adjusted R2 = 0.30). Physiological PC2 (handgrip strength) was mainly explained by combined plasma PC1-sex variable (adjusted R2 = 0.54), with minimal contribution from behavioral factors. RT was associated with physiological PC1 variable and sex (adjusted R2 = 0.35), with slower responses observed among women with lower physiological PC1 scores or hypotension; these associations were supported by RT-physiological PC1 and RT-blood pressure correlations. These exploratory findings suggest sex-dependent associations between physiological, metabolic and lifestyle-related factors, supporting a holistic approach in future research, particularly among young adults.

physiology↗

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↗

bioRxiv2025

Neuropilin-1 expression by solid tumors impairs CAR T cell function

Neuropilin-1 (NRP-1) is a versatile transmembrane protein expressed in numerous cell types and tissues, both in health and in disease. In particular, it is expressed by activated T cells, where it has been shown to play an inhibitory role, dampening their response to tumor cells. Chimeric antigen receptor (CAR) T cells have had considerable success in treating cancers such as B cell leukemias, but face several obstacles in the treatment of solid tumors. We hypothesized that NRP-1 may contribute to dampening CAR T cell responses to cancer. While NRP-1 blockade either through neutralizing antibodies or through CRISPR/Cas9-mediated deletion did not improve CAR T cell cytotoxic activity in an in vitro solid tumor model, NRP-1 was found to have a protective effect against CAR T cells when expressed by the tumor cells, in line with previous literature implicating NRP-1 as a pro-tumor factor involved in their growth and invasiveness. We found that NRP-1 was transferred from target cells to CAR T cells via trogocytosis, i.e. the "nibbling" and subsequent display of membrane proteins from one cell by another. CD19, the target antigen in this model, was also transferred to CAR T cells, raising interesting questions about trogocytosis as a marker for effective tumor cell killing through direct interaction. On the contrary, trogocytosis may impede effective CAR T function by promoting fratricide due to their display of target antigen. While no conclusive mechanisms for NRP-1 activity were found, several avenues of research have been opened up to further our understanding of the multifaceted roles of NRP-1 in CAR T cell activity and interactions with their targets.

immunology↗

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↗

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↗