Biology subjects

Fuentes, P.

Publications and source records attributed to Fuentes, P..

5 recordsLinked to original sources

bioRxiv2024

Pre-TCR-Targeted Immunotherapy for T-cell Acute Lymphoblastic Leukemia

Targeted immunotherapy for T-cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T-cell progenitors, is an urgent unmet need, especially for relapsed/refractory (r/r) disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-TCR, a surface receptor essential for T-cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patients xenografts. Furthermore, we demonstrate the specific therapeutic targeting of pre-TCR with a monoclonal antibody against the invariant pT subunit of the human pre-TCR, and validate an anti-pT antibody-drug conjugate treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in vivo. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of (r/r) patients with T-ALL expressing the pre-TCR.

immunology↗

bioRxiv2024

Combined Dendritic Cell And Anti-TIGIT Immunotherapy Potentiate Trail+ Memory NK Cells Against HIV-1 Infected Cells

Natural Killer (NK) cells are promising tools for the development of immunotherapies targeting persistently infected CD4+ T cells to potentially achieve remission in people with HIV-1 (PWH). However, the chronicity of HIV-1 infection limits the functional properties of NK cells, and additional approaches are needed to potentiate their cytotoxic activity against HIV-1-infected cells. In the present study, we analyzed the reinvigoration of functional NK cells from PWH after priming with autologous dendritic cells (DC) stimulated with nanoparticles containing Poly I:C (Nano-PIC). We show that improved natural cytotoxic function in NK cell from PWH associates with increased proportions of NKG2C+CD57- precursors of memory NK, which eliminate HIV-1 infected CD4+ T cells mainly through the TRAIL receptor. In addition, expression of TIGIT but not TIM3 limited increase in NKG2C+ memory NK cell precursors and associated with persistent dysfunctionality of NK cells after stimulation with Nano PIC-DC. Blockade of TIGIT restored functional capacities of NK cell from PWH eliminating HIV-1 infected cells in vitro. Moreover, combining of NK cell and Nano-PIC-DC with anti-TIGIT mAbs immunotherapy limited the expansion of HIV-1 infected cells in humanized immunodeficient NSG mice transplanted with CD4+ T cells from PWH in vivo. Such viral control was associated with preserved NKG2C memory NK cell precursors, increased expression of granzyme B and TRAIL on NK in tissue from transplanted NSG mice. Together, combination of Nano-PIC DC and anti-TIGIT antibodies may be a promising strategy to increase the efficacy of immunotherapies aimed at HIV-1 cure. One sentence summaryStimulation of memory NK with a combination of DC and anti-TIGIT antibodies increase their ability to eliminate HIV-1 infected CD4+ T cells in vitro and in vivo.

immunology↗

bioRxiv2023

Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis

Lymphoid tumor patients often exhibit resistance to standard therapies or experience rapid relapse post-remission. Tumor-initiating cells (TICs), a small fraction of the tumor cell population known for their self-renewal capacity and resistance to cancer therapies, likely drive tumor relapse. Tumorigenicity strongly correlates with growth in soft gels and TICs are the only cancer cells capable of growing in soft gels. Targeting pathways critical for TIC survival or growth holds promise for improving cancer treatment outcomes but TIC biology remains poorly understood. Here, we show that culturing lymphoid cells in soft hydrogels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and even promotes the growth of primary non-tumor lymphoid cells in soft gels. Some lymphoma cells escape ROS-induced lethality by boosting antioxidant glutathione production, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell viability and proliferation in soft gels and tumor growth in immunodeficient mice. Tumor cells from B-cell lymphoma/leukemia patients and {lambda}-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female {lambda}-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.

cancer biology↗

bioRxiv2023

Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution

Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and could be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at the baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.

genomics↗

bioRxiv2022

Production of selenium nanoparticles occurs through an interconnected pathway of sulfur metabolism and oxidative stress response in Pseudomonas putida KT2440

The soil bacterium Pseudomonas putida KT2440 has been shown to produce selenium nanoparticles aerobically from selenite; however, the molecular actors involved in this process are unknown. Here, through a combination of genetic and analytical techniques, we report the first insights into selenite metabolism in this bacterium. Our results suggest that the reduction of selenite occurs through an interconnected metabolic network involving central metabolic reactions, sulfur metabolism, and the response to oxidative stress. Genes such as sucA, D2HGDH and PP_3148 revealed that the 2-ketoglutarate and glutamate metabolism is important to converting selenite into selenium. On the other hand, mutants affecting the activity of sulfite reductase reduced the bacterias ability to transform selenite. Other genes related to sulfur metabolism (ssuEF, sfnCE, sqrR, sqr and pdo2) and stress response (gqr, lsfA, ahpCF and sadI) were also identified as involved in selenite transformations. Interestingly, suppression of genes sqrR, sqr and pdo2 resulted in the production of selenium nanoparticles at a higher rate than the wild-type strain, which is of biotechnological interest. The data provided in this study brings us closer to understanding the metabolism of selenium in bacteria, and offers new targets for the development of biotechnological tools for the production of selenium nanoparticles.

microbiology↗