bims-imseme 2021-01-03 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2021–01–03
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Similarities and interplay between senescent cells and macrophages.
An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection.
NAD+ metabolism and its roles in cellular processes during ageing.
Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy.
The Proteomic Landscape of Resting and Activated CD4+ T Cells Reveal Insights into Cell Differentiation and Function.
The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases.
The glutaminase inhibitor CB-839 (Telaglenastat) enhances the anti-melanoma activity of T cell mediated immunotherapies.
Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy.
Is exercise a senolytic medicine? A systematic review.
Hypoxia-inducible factor 1 alpha limits dendritic cell stimulation of CD8 T cell immunity.
Mitophagy: A New Player in Stem Cell Biology.

J Cell Biol. 2021 Feb 01. pii: e202010162. [Epub ahead of print]220(2):

Similarities and interplay between senescent cells and macrophages.

Jacques Behmoaras, Jesús Gil.

Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage-senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

DOI: https://doi.org/10.1083/jcb.202010162
Free Radic Biol Med. 2020 Dec 28. pii: S0891-5849(20)31672-5. [Epub ahead of print]163 268-280

An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection.

Y Ana, J D Rojas Marquez, L Fozzatti, R E Baigorrí, C Marin, B A Maletto, F M Cerbán, R Radi, L Piacenza, C C Stempin.

  Chagas disease caused by Trypanosoma cruzi parasite is an endemic infection in America. It is well known that T. cruzi causes a strong immunosuppression during the acute phase of infection. However, it is not clear whether T. cruzi infection is related to metabolic alterations in CD4 T cells that prevent downstream effector function. Here, we evaluated the CD4 T cell metabolic and mitochondrial profiles from non-infected (NI), acute phase (AP) and chronic phase (CP) T. cruzi infected mice. CD4 T cells from all groups showed increased glucose uptake after stimulation. Moreover, the bioenergetic analysis revealed a rise in glycolysis and a higher oxidative metabolism in CD4 T cells from the AP. These cells showed increased proton leak and uncoupling protein 3 (UCP3) expression that correlated with mitochondrial ROS (mROS) accumulation, mitochondrial membrane potential (MMP) depolarization and expression of PD-1. In addition, CD4 T cells with mitochondrial alteration displayed an activated phenotype, and were less functional and more prone to apoptosis. In contrast, mitochondrial alterations were not observed during in vivo activation of CD4 T cells in a model of OVA-immunization. The Mn-superoxide dismutase (SOD2) expression, which is involved in mROS detoxification, was increased during the AP and CP of infection. Remarkably, the apoptosis observed in CD4 T cells with MMP depolarization was prevented by incubation with N-acetyl cysteine (NAC). Thus, our results showed that infection triggered an exacerbated metabolism together with mROS production in CD4 T cells from the AP of infection. However, antioxidant availability may not be sufficient to avoid mitochondrial alterations rendering these cells more susceptible to apoptosis. Our investigation is the first to demonstrate an association between a disturbed metabolism and an impaired CD4 T cell response during T. cruzi infection.

Keywords:  CD4 T cell; Metabolism; Mitochondria; ROS; Trypanosoma cruzi

DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.009
Nat Rev Mol Cell Biol. 2020 Dec 22.

NAD+ metabolism and its roles in cellular processes during ageing.

Anthony J Covarrubias, Rosalba Perrone, Alessia Grozio, Eric Verdin.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

DOI: https://doi.org/10.1038/s41580-020-00313-x
Cells. 2020 Dec 24. pii: E14. [Epub ahead of print]10(1):

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy.

Marsha Pellegrino, Francesca Del Bufalo, Biagio De Angelis, Concetta Quintarelli, Ignazio Caruana, Emmanuel de Billy.

  The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.

Keywords:  Chimeric Antigen Receptor T cells; cancer; combined therapy; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.3390/cells10010014
Int J Mol Sci. 2020 Dec 29. pii: E275. [Epub ahead of print]22(1):

The Proteomic Landscape of Resting and Activated CD4+ T Cells Reveal Insights into Cell Differentiation and Function.

Yashwanth Subbannayya, Markus Haug, Sneha M Pinto, Varshasnata Mohanty, Hany Zakaria Meås, Trude Helen Flo, T S Keshava Prasad, Richard K Kandasamy.

  CD4+ T cells (T helper cells) are cytokine-producing adaptive immune cells that activate or regulate the responses of various immune cells. The activation and functional status of CD4+ T cells is important for adequate responses to pathogen infections but has also been associated with auto-immune disorders and survival in several cancers. In the current study, we carried out a label-free high-resolution FTMS-based proteomic profiling of resting and T cell receptor-activated (72 h) primary human CD4+ T cells from peripheral blood of healthy donors as well as SUP-T1 cells. We identified 5237 proteins, of which significant alterations in the levels of 1119 proteins were observed between resting and activated CD4+ T cells. In addition to identifying several known T-cell activation-related processes altered expression of several stimulatory/inhibitory immune checkpoint markers between resting and activated CD4+ T cells were observed. Network analysis further revealed several known and novel regulatory hubs of CD4+ T cell activation, including IFNG, IRF1, FOXP3, AURKA, and RIOK2. Comparison of primary CD4+ T cell proteomic profiles with human lymphoblastic cell lines revealed a substantial overlap, while comparison with mouse CD+ T cell data suggested interspecies proteomic differences. The current dataset will serve as a valuable resource to the scientific community to compare and analyze the CD4+ proteome.

Keywords:  CD4+ T helper cells; T-lymphocytes; adaptive immunity; label-free quantitation; mass spectrometry; proteomics; systems biology

DOI:  https://doi.org/10.3390/ijms22010275
Biology (Basel). 2020 Dec 21. pii: E485. [Epub ahead of print]9(12):

The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases.

Lorenzo Cuollo, Fabrizio Antonangeli, Angela Santoni, Alessandra Soriani.

  Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called "senomorphics". In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

Keywords:  SASP; age-related disease; cancer therapy; inflammation; senescence; senolytic; senomorphic

DOI:  https://doi.org/10.3390/biology9120485
Mol Cancer Ther. 2020 Dec 23. pii: molcanther.0430.2020. [Epub ahead of print]

The glutaminase inhibitor CB-839 (Telaglenastat) enhances the anti-melanoma activity of T cell mediated immunotherapies.

Sruthy Varghese, Snigdha Pramanik, Leila J Williams, Hannah R Hodges, Courtney W Hudgens, Grant M Fischer, Catherine K Luo, Barbara Knighton, Lin Tan, Philip L Lorenzi, Andrew L MacKinnon, Jennifer L McQuade, Yared Hailemichael, Jason Roszik, Weiyi Peng, Y N Vashisht Gopal.

Immune checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of melanoma patients. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. While numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses. In this study, we evaluated the anti-melanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a potent glutaminase inhibitor (GLSi) that has favorable systemic tolerance. In in vitro TIL:tumor co-culture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs in these co-cultures. These results suggest that CB-839 may improve immune function in a tumor microenvironment by differentially altering tumor and immune cell metabolism. In vivo CB-839 treatment activated melanoma antigen-specific T cells, and improved their tumor killing activity in an immune-competent mouse model of adoptive T cell therapy. Additionally, combination of CB-839 with anti-PD1 or anti-CTLA4 antibodies increased tumor infiltration by effector T cells and improved the anti-tumor activity of these checkpoint inhibitors in a high mutation burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNγ)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.

DOI: https://doi.org/10.1158/1535-7163.MCT-20-0430
Front Cell Dev Biol. 2020 ;8 603292

Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy.

Amina Mohammadalipour, Sandeep P Dumbali, Pamela L Wenzel.

  Mesenchymal stromal cell (MSC) metabolism plays a crucial role in the surrounding microenvironment in both normal physiology and pathological conditions. While MSCs predominantly utilize glycolysis in their native hypoxic niche within the bone marrow, new evidence reveals the importance of upregulation in mitochondrial activity in MSC function and differentiation. Mitochondria and mitochondrial regulators such as sirtuins play key roles in MSC homeostasis and differentiation into mature lineages of the bone and hematopoietic niche, including osteoblasts and adipocytes. The metabolic state of MSCs represents a fine balance between the intrinsic needs of the cellular state and constraints imposed by extrinsic conditions. In the context of injury and inflammation, MSCs respond to reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), such as damaged mitochondria and mitochondrial products, by donation of their mitochondria to injured cells. Through intercellular mitochondria trafficking, modulation of ROS, and modification of nutrient utilization, endogenous MSCs and MSC therapies are believed to exert protective effects by regulation of cellular metabolism in injured tissues. Similarly, these same mechanisms can be hijacked in malignancy whereby transfer of mitochondria and/or mitochondrial DNA (mtDNA) to cancer cells increases mitochondrial content and enhances oxidative phosphorylation (OXPHOS) to favor proliferation and invasion. The role of MSCs in tumor initiation, growth, and resistance to treatment is debated, but their ability to modify cancer cell metabolism and the metabolic environment suggests that MSCs are centrally poised to alter malignancy. In this review, we describe emerging evidence for adaptations in MSC bioenergetics that orchestrate developmental fate decisions and contribute to cancer progression. We discuss evidence and potential strategies for therapeutic targeting of MSC mitochondria in regenerative medicine and tissue repair. Lastly, we highlight recent progress in understanding the contribution of MSCs to metabolic reprogramming of malignancies and how these alterations can promote immunosuppression and chemoresistance. Better understanding the role of metabolic reprogramming by MSCs in tissue repair and cancer progression promises to broaden treatment options in regenerative medicine and clinical oncology.

Keywords:  MSC differentiation; cancer metabolism; hematological malignancy; mesenchymal stromal cells (MSCs); metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial transfer

DOI:  https://doi.org/10.3389/fcell.2020.603292
Aging Cell. 2020 Dec 30. e13294

Is exercise a senolytic medicine? A systematic review.

Xiang-Ke Chen, Zhen-Ni Yi, Gordon Tin-Chun Wong, Kazi Md Mahmudul Hasan, Joseph Shiu-Kwong Kwan, Alvin Chun-Hang Ma, Raymond Chuen-Chung Chang.

  Cellular senescence, a state of irreversible growth arrest triggered by various stressors, engages in a category of pathological processes, whereby senescent cells accumulate in mitotic tissues. Senolytics as novel medicine against aging and various diseases through the elimination of senescent cells has emerged rapidly in recent years. Exercise is a potent anti-aging and anti-chronic disease medicine, which has shown the capacity to lower the markers of cellular senescence over the past decade. However, whether exercise is a senolytic medicine for aging and various diseases remains unclear. Here, we have conducted a systematic review of the published literature studying the senolytic effects of exercise or physical activity on senescent cells under various states in both human and animal models. Exercise can reduce the markers of senescent cells in healthy humans, while it lowered the markers of senescent cells in obese but not healthy animals. The discrepancy between human and animal studies may be due to the relatively small volume of research and the variations in markers of senescent cells, types of cells/tissues, and health conditions. These findings suggest that exercise has senolytic properties under certain conditions, which warrant further investigations.

Keywords:  cellular senescence; exercise; senescent cells; senolytic medicine; senolytics

DOI:  https://doi.org/10.1111/acel.13294
PLoS One. 2020 ;15(12): e0244366

Hypoxia-inducible factor 1 alpha limits dendritic cell stimulation of CD8 T cell immunity.

Charles W Tran, Matthew J Gold, Carlos Garcia-Batres, Kelly Tai, Alisha R Elford, Megan E Himmel, Andrew J Elia, Pamela S Ohashi.

Dendritic cells are sentinels of the immune system and represent a key cell in the activation of the adaptive immune response. Hypoxia-inducible factor 1 alpha (HIF-1α)-a crucial oxygen sensor stabilized during hypoxic conditions-has been shown to have both activating and inhibitory effects in immune cells in a context- and cell-dependent manner. Previous studies have demonstrated that in some immune cell types, HIF-1α serves a pro-inflammatory role. Genetic deletion of HIF-1α in macrophages has been reported to reduce their pro-inflammatory function. In contrast, loss of HIF-1α enhanced the pro-inflammatory activity of dendritic cells in a bacterial infection model. In this study, we aimed to further clarify the effects of HIF-1α in dendritic cells. Constitutive expression of HIF-1α resulted in diminished immunostimulatory capacity of dendritic cells in vivo, while conditional deletion of HIF-1α in dendritic cells enhanced their ability to induce a cytotoxic T cell response. HIF-1α-expressing dendritic cells demonstrated increased production of inhibitory mediators including IL-10, iNOS and VEGF, which correlated with their reduced capacity to drive effector CD8+ T cell function. Altogether, these data reveal that HIF-1α can promote the anti-inflammatory functions of dendritic cells and provides insight into dysfunctional immune responses in the context of HIF-1α activation.

DOI: https://doi.org/10.1371/journal.pone.0244366
Biology (Basel). 2020 Dec 19. pii: E481. [Epub ahead of print]9(12):

Mitophagy: A New Player in Stem Cell Biology.

George Cairns, Madhavee Thumiah-Mootoo, Yan Burelle, Mireille Khacho.

  The fundamental importance of functional mitochondria in the survival of most eukaryotic cells, through regulation of bioenergetics, cell death, calcium dynamics and reactive oxygen species (ROS) generation, is undisputed. However, with new avenues of research in stem cell biology these organelles have now emerged as signaling entities, actively involved in many aspects of stem cell functions, including self-renewal, commitment and differentiation. With this recent knowledge, it becomes evident that regulatory pathways that would ensure the maintenance of mitochondria with state-specific characteristics and the selective removal of organelles with sub-optimal functions must play a pivotal role in stem cells. As such, mitophagy, as an essential mitochondrial quality control mechanism, is beginning to gain appreciation within the stem cell field. Here we review and discuss recent advances in our knowledge pertaining to the roles of mitophagy in stem cell functions and the potential contributions of this specific quality control process on to the progression of aging and diseases.

Keywords:  metabolism; mitochondria; mitochondrial quality control; mitophagy; self-renewal; stem cells

DOI:  https://doi.org/10.3390/biology9120481