Biology subjects

Velica, P.

Publications and source records attributed to Velica, P..

5 recordsLinked to original sources

bioRxiv2022

Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

SummaryOxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.

immunology↗

bioRxiv2022

Glutarate regulates T cell function and metabolism

T cell function is influenced by several metabolites; some acting through enzymatic inhibition of -KG-dependent dioxygenases (KGDDs), others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, with effects on T cell function and differentiation. Glutarate exerts those effects through KGDD inhibition and through direct regulation of T cell metabolism via post-translational modification of the pyruvate dehydrogenase E2 subunit. Diethyl-glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound reduces tumor growth and is correlated with increased levels of both peripheral and intratumoral cytotoxic CD8+ T cells. These results demonstrate that glutarate regulates both T cell metabolism and differentiation, with a potential role in the improvement of T cell immunotherapy.

immunology↗

bioRxiv2021

Lactate regulation of activation in CD8+ T cells

CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in tissues can result in extended exposure of cytotoxic T cells to the metabolite lactate. Lactate can be immunosuppressive, at least in part due to its association with tissue acidosis. We show here that the lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and is capable of displacing glucose as a carbon source. Activation in the presence of a pH neutral form of lactate significantly alters the CD8+ T cell transcriptome, including the expression of key effector differentiation markers such as granzyme B and interferon-gamma. Our studies reveal the novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.

immunology↗

bioRxiv2020

Modified HIF expression in CD8+ T cells increases anti-tumor efficacy

Adoptive transfer of anti-tumor cytotoxic T cells is a novel form of cancer immunotherapy, and a key challenge is to ensure the survival and function of the transferred T cells. Immune cell survival requires adaptation to different micro-environments, and particularly to the hypoxic milieu of solid tumors. The HIF transcription factors are an essential aspect of this adaptation, and we undertook experiments to define structural determinants of HIF that would potentiate anti-tumor efficacy in cytotoxic T cells. We created retroviral vectors to deliver ectopic expression of HIF-1ɑ and HIF-2ɑ in mouse CD8+ T cells, together or individually, and with or without sensitivity to their oxygen-dependent inhibitors Von Hippel-Lindau (VHL) and Factor Inhibiting HIF (FIH). We found that HIF-2ɑ, but not HIF-1ɑ, drives broad transcriptional changes in CD8+ T cells, resulting in increased cytotoxic differentiation and cytolytic function against tumor targets. We further found that a specific mutation replacing the hydroxyl group acceptor site for FIH in the HIF-2ɑ isoform gives rise to the most effective anti-tumor T cells after adoptive transfer in vivo. Lastly, we show that co-delivering an FIH-insensitive form of HIF-2ɑ with an anti-CD19 chimeric antigen receptor greatly enhances cytolytic function of human CD8+ T cells against lymphoma cells. These experiments provide a means to increase the anti-tumor efficacy of therapeutic CD8+ T cells via ectopic expression of the HIF transcription factor.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2019

Lactate potentiates differentiation and expansion of cytotoxic T cells

Exercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumour progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumour growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that injection of lactate into animals can reduce malignant tumour growth in a dose-and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to increase the anti-tumour activity of cytotoxic T cells, and in so doing, reduce cancer progression.

immunology↗