bims-imseme 2021-02-21 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2021‒02‒21
twenty-one papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases.
Diverse Roles of Akt in T cells.
FOXO1 constrains activation and regulates senescence in CD8 T cells.
Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.
Mechanisms of regulate gene expression during immune cell differentiation and development: Conversations that count: Cellular interactions that drive T cell fate.
Hallmarks of the aging T cell system.
Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults.
Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling.
Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.
Mitochondrial Dynamics in the Drosophila Ovary Regulates Germ Stem Cell Number, Cell Fate, and Female Fertility.
Genetic engineering of T cells for immunotherapy.
Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation.
Features of T-cell subset composition in a D-galactose-induced senescence mouse model.
The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters.
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling.
The Roles of mitochondrial dysfunction and Reactive Oxygen Species in Aging and Senescence.
CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours.
Tackling cancer cell dormancy: Insights from immune models, and transplantation.
Inactivation of the PD-1-Dependent Immunoregulation in Mice Exacerbates Contact Hypersensitivity Resembling Immune-Related Adverse Events.
The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells.

Ageing Res Rev. 2021 Feb 10. pii: S1568-1637(21)00027-1. [Epub ahead of print]67 101280

Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases.

Antero Salminen.

  Aging is a progressive degenerative process involving a chronic low-grade inflammation and the accumulation of senescent cells. One major issue is to reveal the mechanisms which promote the deposition of pro-inflammatory senescent cells within tissues. The accumulation involves mechanisms which increase cellular senescence as well as those inhibiting the clearance of senescent cells from tissues. It is known that a persistent inflammatory state evokes a compensatory immunosuppression which inhibits pro-inflammatory processes by impairing the functions of effector immune cells, e.g., macrophages, T cells and natural killer (NK) cells. Unfortunately, these cells are indispensable for immune surveillance and the subsequent clearance of senescent cells, i.e., the inflammation-induced counteracting immunosuppression prevents the cleansing of host tissues. Moreover, senescent cells can also repress their own clearance by expressing inhibitors of immune surveillance and releasing the ligands of NKG2D receptors which impair their surveillance by NK and cytotoxic CD8+ T cells. It seems that cellular senescence and immunosuppression establish a feed-forward process which promotes the aging process and age-related diseases. I will examine in detail the immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging. In addition, I will discuss several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases.

Keywords:  Ageing; Alzheimer’s; Anti-inflammatory; Immunometabolism; Immunosenescence; Inflammaging; SASP

DOI:  https://doi.org/10.1016/j.arr.2021.101280
Immunometabolism. 2021 ;pii: e210007. [Epub ahead of print]3(1):

Diverse Roles of Akt in T cells.

Leena Abdullah, L Benjamin Hills, Evan B Winter, Yina H Huang.

  Akt kinases translate various external cues into intracellular signals that control cell survival, proliferation, metabolism and differentiation. This review discusses the requirement for Akt and its targets in determining the fate and function of T cells. We discuss the importance of Akt at various stages of T cell development including β-selection during which Akt fulfills the energy requirements of highly proliferative DN3 cells. Akt also plays an integral role in CD8 T cell biology where its regulation of Foxo transcription factors and mTORC1 metabolic activity controls effector versus memory CD8 T cell differentiation. Finally, Akt promotes the differentiation of naïve CD4 T cells into Th1, Th17 and Tfh cells but inhibits the development of Treg cells. We also highlight how modulating Akt in T cells is a promising avenue for enhancing cell-based cancer immunotherapy.

Keywords:  Akt; CD8 T cells; Foxo; T cell differentiation; Tfh; Th1; Th17; Treg; mTOR; thymocytes

DOI:  https://doi.org/10.20900/immunometab20210007
Cell Rep. 2021 Jan 26. pii: S2211-1247(20)31663-6. [Epub ahead of print]34(4): 108674

FOXO1 constrains activation and regulates senescence in CD8 T cells.

Arnaud Delpoux, Nimi Marcel, Rodrigo Hess Michelini, Carol D Katayama, Karmel A Allison, Christopher K Glass, Sergio M Quiñones-Parra, Cornelis Murre, Liyen Loh, Katherine Kedzierska, Martha Lappas, Stephen M Hedrick, Andrew L Doedens.

  Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence. Age-based analysis of human peripheral T cells reveals that levels of FOXO1 and its downstream target, TCF7, are inversely related to host age, whereas the opposite is found for AP-1 factors. These characteristics of aging also correlate with the formation of T cells manifesting features of cellular senescence. Our work illustrates a role for FOXO1 in the active maintenance of stem-like properties in T cells at the timescales of acute infection and organismal life span.

Keywords:  AP-1; CD8; FOXO1; T cells; aging; effector; immune senescence; memory; multipotency; quiescence

DOI:  https://doi.org/10.1016/j.celrep.2020.108674
J Clin Invest. 2021 Feb 15. pii: 140100. [Epub ahead of print]131(4):

Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.

Deanna N Edwards, Verra M Ngwa, Ariel L Raybuck, Shan Wang, Yoonha Hwang, Laura C Kim, Sung Hoon Cho, Yeeun Paik, Qingfei Wang, Siyuan Zhang, H Charles Manning, Jeffrey C Rathmell, Rebecca S Cook, Mark R Boothby, Jin Chen.

  Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.

Keywords:  Amino acid metabolism; Breast cancer; Cancer immunotherapy; Oncology

DOI:  https://doi.org/10.1172/JCI140100
Immunol Rev. 2021 Feb 14.

Mechanisms of regulate gene expression during immune cell differentiation and development: Conversations that count: Cellular interactions that drive T cell fate.

Brigette C Duckworth, Joanna R Groom.

  The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen-presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (TFH ) cells and CD8+ central memory stem-like (TSCM ) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T-helper 1 (TH1 ) and CD8+ short-lived effector (TSLEC ) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases.

Keywords:  T cell differentiation; T follicular helper; cellular interactions; lymphoid niche; migration; stem-like memory; transcriptional regulation

DOI:  https://doi.org/10.1111/imr.12945
FEBS J. 2021 Feb 16.

Hallmarks of the aging T cell system.

Huimin Zhang, Cornelia M Weyand, Jörg J Goronzy.

  The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th -10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.

Keywords:  Immunosenescence; T cell aging; T cell differentiation; T cell homeostasis; adaptive immunity; cellular senescence

DOI:  https://doi.org/10.1111/febs.15770
Immun Ageing. 2021 Feb 13. 18(1): 6

Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults.

Stephanie M Dillon, Tezha A Thompson, Allison J Christians, Martin D McCarter, Cara C Wilson.

  BACKGROUND: The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons.RESULTS: Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults.
CONCLUSIONS: Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

Keywords:  Aging; CD4 T cells; CD8 T cells; Gut; Human; Tissue resident memory T cells

DOI:  https://doi.org/10.1186/s12979-021-00217-0
Protein Cell. 2021 Feb 19.

Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling.

Juanjuan Yuan, Ting Cai, Xiaojun Zheng, Yangzi Ren, Jingwen Qi, Xiaofei Lu, Huihui Chen, Huizhen Lin, Zijie Chen, Mengnan Liu, Shangwen He, Qijun Chen, Siyang Feng, Yingjun Wu, Wei Yang, Yanqing Ding, Zhenhai Zhang.

  Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells: LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.

Keywords:  CD8+ T cells; LDLR; PCSK9; TCR; cancer immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1007/s13238-021-00821-2
Nature. 2021 Feb 15.

Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

McLane J Watson, Paolo D A Vignali, Steven J Mullett, Abigail E Overacre-Delgoffe, Ronal M Peralta, Stephanie Grebinoski, Ashley V Menk, Natalie L Rittenhouse, Kristin DePeaux, Ryan D Whetstone, Dario A A Vignali, Timothy W Hand, Amanda C Poholek, Brett M Morrison, Jeffrey D Rothstein, Stacy G Wendell, Greg M Delgoffe.

Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4-6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

DOI: https://doi.org/10.1038/s41586-020-03045-2
Front Cell Dev Biol. 2020 ;8 596819

Mitochondrial Dynamics in the Drosophila Ovary Regulates Germ Stem Cell Number, Cell Fate, and Female Fertility.

Marcia Garcez, Joana Branco-Santos, Patricia C Gracio, Catarina C F Homem.

  The fate and proliferative capacity of stem cells have been shown to strongly depend on their metabolic state. Mitochondria are the powerhouses of the cell being responsible for energy production via oxidative phosphorylation (OxPhos) as well as for several other metabolic pathways. Mitochondrial activity strongly depends on their structural organization, with their size and shape being regulated by mitochondrial fusion and fission, a process known as mitochondrial dynamics. However, the significance of mitochondrial dynamics in the regulation of stem cell metabolism and fate remains elusive. Here, we characterize the role of mitochondria morphology in female germ stem cells (GSCs) and in their more differentiated lineage. Mitochondria are particularly important in the female GSC lineage. Not only do they provide these cells with their energy requirements to generate the oocyte but they are also the only mitochondria pool to be inherited by the offspring. We show that the undifferentiated GSCs predominantly have fissed mitochondria, whereas more differentiated germ cells have more fused mitochondria. By reducing the levels of mitochondrial dynamics regulators, we show that both fused and fissed mitochondria are required for the maintenance of a stable GSC pool. Surprisingly, we found that disrupting mitochondrial dynamics in the germline also strongly affects nurse cells morphology, impairing egg chamber development and female fertility. Interestingly, reducing the levels of key enzymes in the Tricarboxylic Acid Cycle (TCA), known to cause OxPhos reduction, also affects GSC number. This defect in GSC self-renewal capacity indicates that at least basal levels of TCA/OxPhos are required in GSCs. Our findings show that mitochondrial dynamics is essential for female GSC maintenance and female fertility, and that mitochondria fusion and fission events are dynamically regulated during GSC differentiation, possibly to modulate their metabolic profile.

Keywords:  Drosophila melanogaster; differentiation; fertility; germ stem cell; mitochondrial dynamics; oogenesis; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fcell.2020.596819
Nat Rev Genet. 2021 Feb 18.

Genetic engineering of T cells for immunotherapy.

Gavin I Ellis, Neil C Sheppard, James L Riley.

Genetically engineered T cell immunotherapies have provided remarkable clinical success to treat B cell acute lymphoblastic leukaemia by harnessing a patient's own T cells to kill cancer, and these approaches have the potential to provide therapeutic benefit for numerous other cancers, infectious diseases and autoimmunity. By introduction of either a transgenic T cell receptor or a chimeric antigen receptor, T cells can be programmed to target cancer cells. However, initial studies have made it clear that the field will need to implement more complex levels of genetic regulation of engineered T cells to ensure both safety and efficacy. Here, we review the principles by which our knowledge of genetics and genome engineering will drive the next generation of adoptive T cell therapies.

DOI: https://doi.org/10.1038/s41576-021-00329-9
Sci Rep. 2021 Feb 17. 11(1): 4030

Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation.

Alexander Roberts, Lindsay Bentley, Tina Tang, Fay Stewart, Chiara Pallini, Joel Juvvanapudi, Graham R Wallace, Alison J Cooper, Aaron Scott, David Thickett, Sebastian T Lugg, Hollie Bancroft, Bridget Hemming, Charlotte Ferris, Gerald Langman, Andrew Robinson, Joanne Chapman, Babu Naidu, Thomas Pinkney, Graham S Taylor, Kristian Brock, Zania Stamataki, Catherine A Brady, S John Curnow, John Gordon, Omar Qureshi, Nicholas M Barnes.

Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1-revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1-to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.

DOI: https://doi.org/10.1038/s41598-021-83612-3
Exp Anim. 2021 Feb 15.

Features of T-cell subset composition in a D-galactose-induced senescence mouse model.

Koji Kawata, Takato Suzuki, Kazunori Ozawa, Miho Sekiguchi.

  Long-term administration of D-galactose induces oxidative stress and accelerates normal age-related changes. Hence, the D-galactose-treated rodent model has been widely used for aging research. In this study, we examined the immunological characteristics, especially CD4+ T-cell subset composition, of D-galactose-induced aging model mice to evaluate the model's utility in immunosenescence studies. The spleens of aging model mice subjected to repeated subcutaneous injections of D-galactose exhibited significant increases in T cells with the memory phenotype (CD62Llow CD44high) and individual T-cell subsets (Th1, Th2, Th17 and Treg). Furthermore, cells with the phenotype of T follicular helper (Tfh) cells were spontaneously increased. The features of T-cell subset composition in D-galactose-treated mice were in close agreement with those observed in normal aged mice and appeared to mimic the currently known normal aging processes associated with T-cell homeostasis. Our results suggest that D-galactose-induced aging models would be useful for immunosenescence studies focusing on T-cell homeostasis and give valuable insight into age-related immune system dysregulation.

Keywords:  D-galactose; T-cell subsets; aging model; immunosenescence

DOI:  https://doi.org/10.1538/expanim.20-0095
Sci Adv. 2021 Feb;pii: eabf0717. [Epub ahead of print]7(8):

The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters.

Florian A Schober, David Moore, Ilian Atanassov, Marco F Moedas, Paula Clemente, Ákos Végvári, Najla El Fissi, Roberta Filograna, Anna-Lena Bucher, Yvonne Hinze, Matthew The, Erik Hedman, Ekaterina Chernogubova, Arjana Begzati, Rolf Wibom, Mohit Jain, Roland Nilsson, Lukas Käll, Anna Wedell, Christoph Freyer, Anna Wredenberg.

Induction of the one-carbon cycle is an early hallmark of mitochondrial dysfunction and cancer metabolism. Vital intermediary steps are localized to mitochondria, but it remains unclear how one-carbon availability connects to mitochondrial function. Here, we show that the one-carbon metabolite and methyl group donor S-adenosylmethionine (SAM) is pivotal for energy metabolism. A gradual decline in mitochondrial SAM (mitoSAM) causes hierarchical defects in fly and mouse, comprising loss of mitoSAM-dependent metabolites and impaired assembly of the oxidative phosphorylation system. Complex I stability and iron-sulfur cluster biosynthesis are directly controlled by mitoSAM levels, while other protein targets are predominantly methylated outside of the organelle before import. The mitoSAM pool follows its cytosolic production, establishing mitochondria as responsive receivers of one-carbon units. Thus, we demonstrate that cellular methylation potential is required for energy metabolism, with direct relevance for pathophysiology, aging, and cancer.

DOI: https://doi.org/10.1126/sciadv.abf0717
Nat Med. 2021 Feb 18.

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Tina Cascone, William N William, Annikka Weissferdt, Cheuk H Leung, Heather Y Lin, Apar Pataer, Myrna C B Godoy, Brett W Carter, Lorenzo Federico, Alexandre Reuben, Md Abdul Wadud Khan, Hitoshi Dejima, Alejandro Francisco-Cruz, Edwin R Parra, Luisa M Solis, Junya Fujimoto, Hai T Tran, Neda Kalhor, Frank V Fossella, Frank E Mott, Anne S Tsao, George Blumenschein, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren Averett Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Mara B Antonoff, Humam Kadara, Cara Haymaker, Chantale Bernatchez, Nadim J Ajami, Robert R Jenq, Padmanee Sharma, James P Allison, Andrew Futreal, Jennifer A Wargo, Ignacio I Wistuba, Stephen G Swisher, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Boris Sepesi.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.

DOI: https://doi.org/10.1038/s41591-020-01224-2
Front Cell Dev Biol. 2020 ;8 620081

Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling.

Andrea Urbani, Elena Prosdocimi, Andrea Carrer, Vanessa Checchetto, Ildikò Szabò.

  Mitochondria are bioenergetic organelles with a plethora of fundamental functions ranging from metabolism and ATP production to modulation of signaling events leading to cell survival or cell death. Ion channels located in the outer and inner mitochondrial membranes critically control mitochondrial function and, as a consequence, also cell fate. Opening or closure of mitochondrial ion channels allow the fine-tuning of mitochondrial membrane potential, ROS production, and function of the respiratory chain complexes. In this review, we critically discuss the intracellular regulatory factors that affect channel activity in the inner membrane of mitochondria and, indirectly, contribute to cell death. These factors include various ligands, kinases, second messengers, and lipids. Comprehension of mitochondrial ion channels regulation in cell death pathways might reveal new therapeutic targets in mitochondria-linked pathologies like cancer, ischemia, reperfusion injury, and neurological disorders.

Keywords:  apoptosis; cell death; cell signaling; ion channel; mitochondria

DOI:  https://doi.org/10.3389/fcell.2020.620081
Curr Mol Med. 2021 Feb 17.

The Roles of mitochondrial dysfunction and Reactive Oxygen Species in Aging and Senescence.

Aliabbas Zia, Tahereh Farkhondeh, Ali Mohammad Pourbagher-Shahri, Saeed Samarghandian.

  The aging process deteriorates organs' function at different levels, causing its progressive decline to resist stress, damage, and disease. In addition to alterations in metabolic control and gene expression, the rate of aging has been connected with the generation of high amounts of Reactive Oxygen Species (ROS). The essential perspective in free radical biology is that reactive oxygen species (ROS) and free radicals are toxic, mostly cause direct biological damage to targets, and are thus a major cause of oxidative stress. Different enzymatic and non-enzymatic compounds in the cells have roles in neutralizing this toxicity. Oxidative damage in aging is mostly high in particular molecular targets, such as mitochondrial DNA and aconitase, and oxidative stress in mitochondria can cause tissue aging across intrinsic apoptosis. Mitochondria's function and morphology are impaired through aging, following a decrease in the membrane potential by an increase in peroxide generation and size of the organelles. Telomeres may be the significant trigger of replicative senescence. Oxidative stress accelerates telomere loss, whereas antioxidants slow it down. Oxidative stress is a crucial modulator of telomere shortening, and that telomere-driven replicative senescence is mainly a stress response. The age-linked mitochondrial DNA mutation and protein dysfunction aggregate in some organs like the brain and skeletal muscle, thus contributing considerably to these post-mitotic tissues' aging. The aging process is mostly due to accumulated damage done by harmful species in some macromolecules such proteins, DNA, and lipids. The degradation of non-functional, oxidized proteins is a crucial part of the antioxidant defenses of cells, in which the clearance of these proteins occurs through autophagy in the cells, which is known as mitophagy for mitochondria.

Keywords:  Aging; Senescence; Mitochondrial dysfunction; Reactive oxygen species

DOI:  https://doi.org/10.2174/1566524021666210218112616
Nature. 2021 Feb 15.

CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours.

Roberta Zappasodi, Inna Serganova, Ivan J Cohen, Masatomo Maeda, Masahiro Shindo, Yasin Senbabaoglu, McLane J Watson, Avigdor Leftin, Rachana Maniyar, Svena Verma, Matthew Lubin, Myat Ko, Mayuresh M Mane, Hong Zhong, Cailian Liu, Arnab Ghosh, Mohsen Abu-Akeel, Ellen Ackerstaff, Jason A Koutcher, Ping-Chih Ho, Greg M Delgoffe, Ronald Blasberg, Jedd D Wolchok, Taha Merghoub.

Limiting the metabolic competition in the tumor microenvironment (TME) may increase the effectiveness of immunotherapy. Because of its critical role in glucose metabolism of activated T cells, CD28 signaling has been proposed as a T-cell metabolic biosensor1. Conversely, CTLA-4 engagement has been shown to down-regulate T-cell glycolysis1. Here, we investigated the impact of CTLA-4 blockade on the metabolic fitness of intra-tumor T cells in relationship to the tumor glycolytic capacity. We found that CTLA-4 blockade promotes immune cell infiltration and metabolic fitness especially in glycolysis-low tumors. Accordingly, anti-CTLA-4 achieved better therapeutic outcomes in mice bearing glycolysis-defective tumors. Intriguingly, tumor-specific CD8+ T-cell responses correlated with phenotypic and functional destabilization of tumor-infiltrating regulatory T cells (Tregs) toward IFN-γ- and TNF-α-producing cells in glycolysis-defective tumors. By mimicking the highly and poorly glycolytic TME in vitro, we show that the effect of CTLA-4 blockade to promote Treg destabilization is dependent on Treg glycolysis and CD28 signaling. These findings indicate that decreasing tumor competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumor glycolysis. Moreover, these results reveal a new mechanism through which anti-CTLA-4 interferes with Treg function in the presence of glucose.

DOI: https://doi.org/10.1038/s41586-021-03326-4
Semin Cancer Biol. 2021 Feb 11. pii: S1044-579X(21)00025-0. [Epub ahead of print]

Tackling cancer cell dormancy: Insights from immune models, and transplantation.

Alexandre Corthay, Tibor Bakacs, Govindarajan Thangavelu, Colin C Anderson.

  Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy.

Keywords:  Cancer dormancy; Coinhibitory; Hyperthermia; Immune tolerance; T cell activation

DOI:  https://doi.org/10.1016/j.semcancer.2021.02.002
Front Immunol. 2020 ;11 618711

Inactivation of the PD-1-Dependent Immunoregulation in Mice Exacerbates Contact Hypersensitivity Resembling Immune-Related Adverse Events.

Matin Dokht Ashoori, Kensuke Suzuki, Yosuke Tokumaru, Naoko Ikuta, Masaki Tajima, Tasuku Honjo, Akio Ohta.

  Blockade of PD-1, an indispensable physiological immunoregulatory mechanism, enhances immune activities and is widely used in the immunotherapy of cancer. This treatment often accompanies inflammatory complication called immune-related adverse events (irAE), most frequently in the skin. To analyze how skin inflammation develops by the blockade of PD-1-dependent immunoregulation, we studied the exacerbation of oxazolone-induced contact hypersensitivity by PD-L1 blockade. The inactivation of PD-1 signaling enhanced swelling of the skin with massive CD8+ T cell infiltration. Among PD-1-expressing cells, T cells were the predominant targets of anti-PD-L1 mAb treatment since PD-L1 blockade did not affect skin inflammation in RAG2-/- mice. PD-L1 blockade during immunization with oxazolone significantly promoted the development of hapten-reactive T cells in the draining lymph nodes. The enhancement of local CD8+ T cell-dominant immune responses by PD-L1 blockade was correlated with the upregulation of CXCL9 and CXCL10. Challenges with a low dose of oxazolone did not demonstrate any significant dermatitis; however, the influence of PD-L1 blockade on T cell immunity was strong enough to cause the emergence of notable dermatitis in this suboptimal dosing, suggesting its relevance to dermal irAE development. In the low-dose setting, the blockade of CXCR3, receptor of CXCL9/10, prevented the induction of T cell-dominant inflammation by anti-PD-L1 mAb. This experimental approach reproduced CD8+ T cell-dominant form of cutaneous inflammation by the blockade of PD-L1 that has been observed in dermal irAE in human patients.

Keywords:  CXCR3; PD-1; T cells; cancer immunotherapy; contact hypersensitivity; immune-related adverse events; skin

DOI:  https://doi.org/10.3389/fimmu.2020.618711
Stem Cell Res Ther. 2021 Feb 17. 12(1): 140

The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells.

Wanhao Yan, Shu Diao, Zhipeng Fan.

  Mesenchymal stem cells (MSCs) are multipotent cells that show self-renewal, multi-directional differentiation, and paracrine and immune regulation. As a result of these properties, the MSCs have great clinical application prospects, especially in the regeneration of injured tissues, functional reconstruction, and cell therapy. However, the transplanted MSCs are prone to ageing and apoptosis and have a difficult to control direction differentiation. Therefore, it is necessary to effectively regulate the functions of the MSCs to promote their desired effects. In recent years, it has been found that mitochondria, the main organelles responsible for energy metabolism and adenosine triphosphate production in cells, play a key role in regulating different functions of the MSCs through various mechanisms. Thus, mitochondria could act as effective targets for regulating and promoting the functions of the MSCs. In this review, we discuss the research status and current understanding of the role and mechanism of mitochondrial energy metabolism, morphology, transfer modes, and dynamics on MSC functions.

Keywords:  Energy metabolism; Mesenchymal stem cells; Mitochondria; Mitochondrial transfer; Reactive oxygen species

DOI:  https://doi.org/10.1186/s13287-021-02194-z