bims-imseme 2020-12-06 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2020‒12‒06
twenty-five papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.
Senescence and the SASP: many therapeutic avenues.
Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells.
Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.
Thymus involution sets the clock of declined immunity and repair with aging.
Mitochondrial Damage and the Road to Exhaustion.
Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging.
Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring "Universal" Donor T Cells.
Metabolic traits ruling the specificity of the immune response in different cancer types.
Antigen-driven CD4+ T-cell anergy: a pathway to peripheral T regulatory cells.
The immunology of rheumatoid arthritis.
Treg cell therapy: how cell heterogeneity can make the difference.
ATG5-dependent autophagy uncouples T cell proliferative and effector functions and separates graft-versus-host disease from graft-versus-leukemia.
Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.
Immunometabolism of regulatory T cells in cancer.
Cellular proteostasis decline in human senescence.
The bright and dark side of skin senescence. Could skin rejuvenation anti-senescence interventions become a "bright" new strategy for the prevention of age-related skin pathologies?
CD103+ cDC1 and endogenous CD8+ T cells are necessary for improved CD40L-overexpressing CAR T cell antitumor function.
Quantitative and functional characteristics of circulating and bone marrow PD-1- and TIM-3-positive T cells in treated multiple myeloma patients.
TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.
Premature CD4+ T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome.
Metabolic regulation of the HBV-specific T cell function.
Starvation and pH stress conditions induced mitochondrial dysfunction, ROS production and autophagy in Trypanosoma cruzi epimastigotes.
Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles.
Memory CD8+ T cell responses to cancer.

Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30598-2. [Epub ahead of print]32(6): 981-995.e7

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.

Mauro Corrado, Joy Edwards-Hicks, Matteo Villa, Lea J Flachsmann, David E Sanin, Maaike Jacobs, Francesc Baixauli, Michal Stanczak, Eve Anderson, Mai Azuma, Andrea Quintana, Jonathan D Curtis, Thomas Clapes, Katarzyna M Grzes, Agnieszka M Kabat, Ryan Kyle, Annette E Patterson, Ramon Klein Geltink, Borko Amulic, Colin G Steward, Douglas Strathdee, Eirini Trompouki, David O'Sullivan, Edward J Pearce, Erika L Pearce.

  Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Keywords:  Barth Syndrome; CD8 T cells; PTPMT1; Tafazzin; cardiolipin; immune memory; immunometabolism; mitochodria

DOI:  https://doi.org/10.1016/j.cmet.2020.11.003
Genes Dev. 2020 Dec 01. 34(23-24): 1565-1576

Senescence and the SASP: many therapeutic avenues.

Jodie Birch, Jesús Gil.

  Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.

Keywords:  SASP; aging; cancer; disease; inflammation; senescence; senolytics; senomorphics; therapeutics

DOI:  https://doi.org/10.1101/gad.343129.120
Front Immunol. 2020 ;11 585168

Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells.

Bin Hu, Rohit R Jadhav, Claire E Gustafson, Sabine Le Saux, Zhongde Ye, Xuanying Li, Lu Tian, Cornelia M Weyand, Jörg J Goronzy.

  Healthy immune aging is in part determined by how well the sizes of naïve T cell compartments are being maintained with advancing age. Throughout adult life, replenishment largely derives from homeostatic proliferation of existing naïve and memory T cell populations. However, while the subpopulation composition of CD4 T cells is relatively stable, the CD8 T cell compartment undergoes more drastic changes with loss of naïve CD8 T cells and accumulation of effector T cells, suggesting that CD4 T cells are more resilient to resist age-associated changes. To determine the epigenetic basis for these differences in behaviors, we compared chromatin accessibility maps of CD4 and CD8 T cell subsets from young and old individuals and related the results to the expressed transcriptome. The dominant age-associated signatures resembled hallmarks of differentiation, which were more pronounced for CD8 naïve and memory than the corresponding CD4 T cell subsets, indicating that CD8 T cells are less able to keep cellular quiescence upon homeostatic proliferation. In parallel, CD8 T cells from old adults, irrespective of their differentiation state, displayed greater reduced accessibility to genes of basic cell biological function, including genes encoding ribosomal proteins. One possible mechanism is the reduced expression of the transcription factors YY1 and NRF1. Our data suggest that chromatin accessibility signatures can be identified that distinguish CD4 and CD8 T cells from old adults and that may confer the higher resilience of CD4 T cells to aging.

Keywords:  T-cell; T-cell homeostasis; aging; chromatin accessibility; epigenetics; ribosomal proteins

DOI:  https://doi.org/10.3389/fimmu.2020.585168
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30594-5. [Epub ahead of print]32(6): 967-980.e5

Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.

Bowen Wu, Jingtao Qiu, Tuantuan V Zhao, Yanan Wang, Toshihisa Maeda, Isabel N Goronzy, Mitsuhiro Akiyama, Shozo Ohtsuki, Ke Jin, Lu Tian, Jörg J Goronzy, Cornelia M Weyand.

  Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoAhi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

Keywords:  T cell; acetyl-CoA; acetylation; alph-ketoglutarate; autoimmunity; citrate; microtubule; mitochondria; tissue invasion; uropod

DOI:  https://doi.org/10.1016/j.cmet.2020.10.025
Ageing Res Rev. 2020 Nov 25. pii: S1568-1637(20)30366-4. [Epub ahead of print] 101231

Thymus involution sets the clock of declined immunity and repair with aging.

Yehezqel Elyahu, Alon Monsonego.

  Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas CD4 T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the CD4 T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated CD4 T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.

Keywords:  Aging; Chronic systemic inflammation; Dysregulated CD4 T cells; Immune-mediated repair; Thymus

DOI:  https://doi.org/10.1016/j.arr.2020.101231
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30599-4. [Epub ahead of print]32(6): 905-907

Mitochondrial Damage and the Road to Exhaustion.

Wenhui Li, Hongcheng Cheng, Guideng Li, Lianjun Zhang.

Two recent studies published in Nature Immunology map out the link between dysregulated mitochondrial metabolism and terminal exhaustion of tumor-infiltrating T lymphocytes. Yu et al. (2020) and Vardhana et al. (2020) show that defective mitophagy or impaired oxidative phosphorylation triggers mitochondrial reactive oxygen species production, which in turn promotes a T cell exhaustion program, limiting T cell proliferation and self-renewal.

DOI: https://doi.org/10.1016/j.cmet.2020.11.004
Immunity. 2020 Nov 21. pii: S1074-7613(20)30492-1. [Epub ahead of print]

Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging.

Denis A Mogilenko, Oleg Shpynov, Prabhakar Sairam Andhey, Laura Arthur, Amanda Swain, Ekaterina Esaulova, Simone Brioschi, Irina Shchukina, Martina Kerndl, Monika Bambouskova, Zhangting Yao, Anwesha Laha, Konstantin Zaitsev, Samantha Burdess, Susan Gillfilan, Sheila A Stewart, Marco Colonna, Maxim N Artyomov.

  Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

Keywords:  Aging; CD8 T cells; CITE-seq; granzyme K; immune system; inflammaging; single-cell ATAC-sequencing; single-cell BCR-sequencing; single-cell RNA-sequencing; single-cell TCR-sequencing

DOI:  https://doi.org/10.1016/j.immuni.2020.11.005
Front Immunol. 2020 ;11 583716

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring "Universal" Donor T Cells.

Cynthia Perez, Isabelle Gruber, Caroline Arber.

  Chimeric antigen receptor (CAR) engineered T cell therapies individually prepared for each patient with autologous T cells have recently changed clinical practice in the management of B cell malignancies. Even though CARs used to redirect polyclonal T cells to the tumor are not HLA restricted, CAR T cells are also characterized by their endogenous T cell receptor (TCR) repertoire. Tumor-antigen targeted TCR-based T cell therapies in clinical trials are thus far using "conventional" αβ-TCRs that recognize antigens presented as peptides in the context of the major histocompatibility complex. Thus, both CAR- and TCR-based adoptive T cell therapies (ACTs) are dictated by compatibility of the highly polymorphic HLA molecules between donors and recipients in order to avoid graft-versus-host disease and rejection. The development of third-party healthy donor derived well-characterized off-the-shelf cell therapy products that are readily available and broadly applicable is an intensive area of research. While genome engineering provides the tools to generate "universal" donor cells that can be redirected to cancers, we will focus our attention on third-party off-the-shelf strategies with T cells that are characterized by unique natural features and do not require genome editing for safe administration. Specifically, we will discuss the use of virus-specific T cells, lipid-restricted (CD1) T cells, MR1-restricted T cells, and γδ-TCR T cells. CD1- and MR1-restricted T cells are not HLA-restricted and have the potential to serve as a unique source of universal TCR sequences to be broadly applicable in TCR-based ACT as their targets are presented by the monomorphic CD1 or MR1 molecules on a wide variety of tumor types. For each cell type, we will summarize the stage of preclinical and clinical development and discuss opportunities and challenges to deliver off-the-shelf targeted cellular therapies against cancer.

Keywords:  CD1; GVHD; MR1; allogeneic off-the-shelf T cells; engineered; rejection; unconventional T cells; virus-specific T cells

DOI:  https://doi.org/10.3389/fimmu.2020.583716
Curr Opin Biotechnol. 2020 Nov 25. pii: S0958-1669(20)30160-9. [Epub ahead of print]68 124-143

Metabolic traits ruling the specificity of the immune response in different cancer types.

Nina C Flerin, Federica Cappellesso, Samantha Pretto, Massimiliano Mazzone.

Cancer immunotherapy aims to augment the response of the patient's own immune system against cancer cells. Despite effective for some patients and some cancer types, the therapeutic efficacy of this treatment is limited by the composition of the tumor microenvironment (TME), which is not well-suited for the fitness of anti-tumoral immune cells. However, the TME differs between cancer types and tissues, thus complicating the possibility of the development of therapies that would be effective in a large range of patients. A possible scenario is that each type of cancer cell, granted by its own mutations and reminiscent of the functions of the tissue of origin, has a specific metabolism that will impinge on the metabolic composition of the TME, which in turn specifically affects T cell fitness. Therefore, targeting cancer or T cell metabolism could increase the efficacy and specificity of existing immunotherapies, improving disease outcome and minimizing adverse reactions.

DOI: https://doi.org/10.1016/j.copbio.2020.10.011
Immunol Cell Biol. 2020 Dec 04.

Antigen-driven CD4+ T-cell anergy: a pathway to peripheral T regulatory cells.

Peter J Eggenhuizen, Boaz H Ng, Joshua D Ooi.

In their recent publication, Kuczma and colleagues have provided evidence that advances the relationship between naive T cells, T cell anergy and T regulatory cells. Their findings strengthen the understanding of how these T cell subsets function in relation to self and microbiota-derived epitopes to promote and maintain peripheral tolerance to self and mucosal antigens.

DOI: https://doi.org/10.1111/imcb.12424
Nat Immunol. 2020 Nov 30.

The immunology of rheumatoid arthritis.

Cornelia M Weyand, Jörg J Goronzy.

The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.

DOI: https://doi.org/10.1038/s41590-020-00816-x
Eur J Immunol. 2020 Dec 04.

Treg cell therapy: how cell heterogeneity can make the difference.

Giulio Giganti, Muhammad Atif, Yasmin Mohseni, Daniela Mastronicola, Nathali Grageda, Giovanni Am Povoleri, Makoto Miyara, Cristiano Scottà.

  CD4+ CD25high CD127low/- FOXP3+ T regulatory (Treg) cells are responsible for maintaining immune tolerance and controlling excessive immune responses. Treg-cell use in pre-clinical animal models showed the huge therapeutic potential of these cells in immune-mediated diseases and laid the foundations for their applications in therapy in humans. Currently, there are several clinical trials utilising the adoptive transfer of Treg-cells to reduce the morbidity in autoimmune disorders, allogeneic hematopoietic stem cell transplantation and solid organ transplantation. However, a large part of them utilises total Treg-cells without distinction of their biological variability. Many studies on the heterogeneity of Treg-cell population revealed distinct subsets with different functions in the control of the immune response and induction of peripheral tolerance. Some of these subsets also showed a role in controlling the general homeostasis of non-lymphoid tissues. All these Treg-cell subsets and their peculiar properties can be therefore exploited to develop novel therapeutic approaches. This review describes these functionally distinct subsets, their phenotype, homing properties and functions in lymphoid and non-lymphoid tissues. In addition, we also discuss the limitations in using Treg-cells as a cellular therapy and the strategies to enhance their efficacy. This article is protected by copyright. All rights reserved.

Keywords:  Regulatory T cells ⋅ Treg subsets ⋅ Cell therapy ⋅ Cell heterogeneity ⋅ Clinical trial

DOI:  https://doi.org/10.1002/eji.201948131
Cancer Res. 2020 Dec 04. pii: canres.1346.2020. [Epub ahead of print]

ATG5-dependent autophagy uncouples T cell proliferative and effector functions and separates graft-versus-host disease from graft-versus-leukemia.

Katherine Oravecz-Wilson, Corinne Rossi, Cynthia Zajac, Yaping Sun, Lu Li, Thomas Decoville, Hideaki Fujiwara, Stephanie Kim, Daniel Peltier, Pavan Reddy.

Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T cell allo-immunity, we generated T cell specific ATG5 knock-out mice. Deficiency of ATG5 dependent autophagy reduced T cell proliferation, increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5 dependent autophagy uncouples T cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1346
Cell Death Dis. 2020 Dec 02. 11(12): 1030

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.

Madison Schank, Juan Zhao, Ling Wang, Zhengke Li, Dechao Cao, Lam Nhat Nguyen, Xindi Dang, Sushant Khanal, Lam Ngoc Thao Nguyen, Bal Krishna Chand Thakuri, Stella C Ogbu, Zeyuan Lu, Jinyu Zhang, Xiao Y Wu, Zheng D Morrison, Mohamed El Gazzar, Shunbin Ning, Jonathan P Moorman, Zhi Q Yao.

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.

DOI: https://doi.org/10.1038/s41419-020-03238-7
Mol Aspects Med. 2020 Nov 26. pii: S0098-2997(20)30138-2. [Epub ahead of print] 100936

Immunometabolism of regulatory T cells in cancer.

Mario Galgani, Sara Bruzzaniti, Claudia La Rocca, Teresa Micillo, Paola de Candia, Maurizio Bifulco, Giuseppe Matarese.

  Regulatory T (Treg) cells are known to orchestrate the regulatory mechanisms aimed at suppressing pathological auto-reactive immune responses and are thus key in ensuring the maintenance of immune homeostasis. On the other hand, the presence of Treg cells with enhanced suppressive capability in a plethora of human cancers represents a major obstacle to an effective anti-cancer immune response. A relevant research effort has thus been dedicated to comprehend Treg cell biology, leading to a continuously refining characterization of their phenotype and function and unveiling the central role of metabolism in ensuring Treg cell fitness in cancer. Here we focus on how the peculiar biochemical characteristics of the tumor microenvironment actually support Treg cell metabolic activation and favor their selective survival and proliferation. Moreover, we examine the key metabolic pathways that may become useful targets of novel treatments directed at hampering tumor resident Treg cell proficiency, thus representing the next research frontier in cancer immunotherapy.

Keywords:  Cancer and tumor microenvironment; Immunometabolism; Treg cells

DOI:  https://doi.org/10.1016/j.mam.2020.100936
Proc Natl Acad Sci U S A. 2020 Nov 30. pii: 202018138. [Epub ahead of print]

Cellular proteostasis decline in human senescence.

Niv Sabath, Flonia Levy-Adam, Amal Younis, Kinneret Rozales, Anatoly Meller, Shani Hadar, Sharon Soueid-Baumgarten, Reut Shalgi.

  Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

Keywords:  UPR; chaperones; heat shock response; protein homeostasis; senescence

DOI:  https://doi.org/10.1073/pnas.2018138117
Mech Ageing Dev. 2020 Nov 26. pii: S0047-6374(20)30205-0. [Epub ahead of print] 111409

The bright and dark side of skin senescence. Could skin rejuvenation anti-senescence interventions become a "bright" new strategy for the prevention of age-related skin pathologies?

Eleni A Georgakopoulou, Christina Valsamidi, Dimitrios Veroutis, Sophia Havaki.

  The number of senescent cells in the skin is increasing with age. Numerous studies have attempted to elucidate the role of these cells in normal aging of the skin as well as in age-related skin conditions. In recent years, attempts have also been made to find treatments that aim either to cleanse the skin tissues of senescent cells or to neutralize their effects (referred to as senolytics and senomorphics respectively) and thus prevent the consequences, particularly on the skin's appearance in advanced age. Through this review, we have tried to gather data on the role of senescent cells in the skin, in treatments aimed at removing them, and we are asking a reasonable question as to whether anti-senescence treatments may contribute to the protection against age-related skin pathologies, including skin cancer, such as non-melanoma skin cancer, in addition to their involvement in skin rejuvenation.

Keywords:  Skin aging; cellular senescence; senolytics

DOI:  https://doi.org/10.1016/j.mad.2020.111409
Nat Commun. 2020 12 02. 11(1): 6171

CD103+ cDC1 and endogenous CD8+ T cells are necessary for improved CD40L-overexpressing CAR T cell antitumor function.

Nicholas F Kuhn, Andrea V Lopez, Xinghuo Li, Winson Cai, Anthony F Daniyan, Renier J Brentjens.

While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3-/- mice lacking the CD103+ conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b-CD103- double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8+ T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses.

DOI: https://doi.org/10.1038/s41467-020-19833-3
Sci Rep. 2020 11 30. 10(1): 20846

Quantitative and functional characteristics of circulating and bone marrow PD-1- and TIM-3-positive T cells in treated multiple myeloma patients.

Egor V Batorov, Tatiana A Aristova, Vera V Sergeevicheva, Svetlana A Sizikova, Galina Y Ushakova, Natalia V Pronkina, Irina V Shishkova, Ekaterina Y Shevela, Alexander A Ostanin, Elena R Chernykh.

The aim of the present work was to evaluate counts and functional properties of PD-1+ and TIM-3+ T cells in peripheral blood (PB) and bone marrow (BM) of multiple myeloma (MM) patients following the induction therapy. Sixty patients were enrolled in the study, CD4+ and CD8+ T cells expressing PD-1 and TIM-3, intracellular production of IFNγ and intracellular expression of Granzyme B were assessed. Relative counts of the majority of circulating PD-1+, TIM-3+ and PD-1+TIM-3+ T cells were higher in MM patients with disease progression compared with individuals in remission. Frequencies of almost all evaluated PD-1+ and TIM-3+ T cell subsets were higher in BM samples compared with PB; circulating CD4+PD-1+, CD8+PD-1+, CD8+TIM-3+, CD8+PD-1+TIM-3+ T cells positively correlated with the same BM subsets. Circulating CD4+ T cells, expressing PD-1 and TIM-3 (including co-expressing subset), as well as CD8+PD-1+TIM-3+ T cells, and BM CD8+PD-1+ T cells correlated with serum B2-M levels. Sufficient frequencies of GrB+ and IFNγ+ subsets in PD-1-expressing T cells indicated their retained functional properties. TIM-3-expressing T cells and double positive PD-1+TIM-3+ populations showed diminished cytotoxic and cytokine-producing ability and therefore might be attributed to the exhausted compartment. To identify T cell exhaustion, it is necessary to evaluate T cells co-expressing PD-1, TIM-3 and other inhibitory signal molecules and to study their functional properties. Sustained functionality of PD-1-positive T cells may explain low efficacy and frequent immune-mediated adverse events during anti-PD-1 therapy in MM.

DOI: https://doi.org/10.1038/s41598-020-77941-y
Cancer Lett. 2020 Nov 27. pii: S0304-3835(20)30633-9. [Epub ahead of print]

TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Hye Sook Han, Seongju Jeong, Hyunglae Kim, Hyung-Don Kim, A Reum Kim, Minsuk Kwon, Su-Hyung Park, Chang Gok Woo, Hee Kyung Kim, Ki Hyeong Lee, Sung Pil Seo, Ho Won Kang, Won Tae Kim, Wun-Jae Kim, Seok Joong Yun, Eui-Cheol Shin.

  Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.

Keywords:  Bladder cancer; CD8(+) T cell; PD-1; TIGIT; TOX

DOI:  https://doi.org/10.1016/j.canlet.2020.11.035
Aging Dis. 2020 Dec;11(6): 1471-1480

Premature CD4+ T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome.

Ming Cao, Lei Ruan, Yi Huang, Jinli Wang, Jinhua Yan, Yu Sang, Shanshan Li, Guan Wang, Xiaofen Wu.

  Acquired immune responses mediated by CD4+ T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4+ T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4+ T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4+CD28null effector T cells and a decline of CD4+CD25+CD62L+Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4+CD45RA+CD62L+ naïve T cells and a compensatory increase in the number of CD4+CD45RO+ memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16Ink4a was increased while CD62L was decreased in CD4+CD28null T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4+CD28+and CD4+CD28null T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, Helicobactor pylori IgG and Chlamydia pneumonia IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4+ T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4+T cells, which may be responsible for the development of ACS.

Keywords:  CD28null T cells; CD4+ T cells; acute coronary syndrome; immunosenescence; infection

DOI:  https://doi.org/10.14336/AD.2020.0203
Antiviral Res. 2020 Nov 25. pii: S0166-3542(20)30403-4. [Epub ahead of print] 104989

Metabolic regulation of the HBV-specific T cell function.

Valeria Barili, Carolina Boni, Marzia Rossi, Andrea Vecchi, Alessandra Zecca, Amalia Penna, Gabriele Missale, Carlo Ferrari, Paola Fisicaro.

  Chronically HBV infected subjects are more than 260 million worldwide; cirrhosis and liver cancer represent possible outcomes which affect around 700,000 patients per year. Both innate and adaptive immune responses are necessary for viral control and both have been shown to be defective in chronic patients. Metabolic remodeling is an essential process in T cell biology, particularly for T cell activation, differentiation and survival. Cellular metabolism relies on the conversion of nutrients into energy to support intracellular processes, and to generate fundamental intermediate components for cell proliferation and growth. Adaptive immune responses are the central mechanisms for the resolution of primary human infections leading to the activation of pathogen-specific B and T cell functions. In chronic HBV infection the anti-viral immune response fails to contain the virus and leads to persistent hepatic tissue damage which may finally result in liver cirrhosis and cancer. This T cell failure is associated with metabolic alterations suggesting that control of nutrient uptake and intracellular utilization as well as correct regulation of intracellular metabolic pathways are strategic for T cell differentiation during persistent chronic infections. This review will discuss some of the main features of the T cell metabolic processes which are relevant to the generation of an efficient antiviral response, with specific focus on their clinical relevance in chronic HBV infection in the perspective of possible strategies to correct deregulated metabolic pathways underlying T cell dysfunction of chronic HBV patients.

Keywords:  CD8+ T cell exhaustion; CD8+ T cell metabolism; Hepatitis B virus; adaptive immunity; chronic HBV infection; metabolic restoration

DOI:  https://doi.org/10.1016/j.antiviral.2020.104989
Biochim Biophys Acta Mol Basis Dis. 2020 Nov 25. pii: S0925-4439(20)30376-8. [Epub ahead of print] 166028

Starvation and pH stress conditions induced mitochondrial dysfunction, ROS production and autophagy in Trypanosoma cruzi epimastigotes.

Yasmin Pedra-Rezende, Michelle C Fernandes, Camila Mesquita-Rodrigues, Renata Stiebler, Ana Cristina S Bombaça, Nathalia Pinho, Patricia Cuervo, Solange L De Castro, Rubem F S Menna-Barreto.

  Chagas disease is a neglected illness endemic in Latin America that mainly affects rural populations. The etiological agent of Chagas disease is the protozoan Trypanosoma cruzi, which has three different parasite stages and a dixenous life cycle that includes colonization of the vertebrate and invertebrate hosts. During its life cycle, T. cruzi is subjected to stress conditions, including variations in nutrient availability and pH, which impact parasite survival and differentiation. The plasticity of mitochondrial function in trypanosomatids has been defined as mitochondrial activity related to substrate availability. Thus, mitochondrial remodeling and autophagy, which is a constitutive cellular process of turnover and recycling of cellular components, may constitute a response to the nutritional and pH stress in the host. To assess these processes, epimastigotes were subjected to acidic, alkaline, and nutritional stress conditions, and mitochondrial function and its influence on the autophagic process were evaluated. Our data demonstrated that the three stress conditions affected the mitochondrial structure, inducing organelle swelling and impaired oxidative phosphorylation. Stressed epimastigotes produced increased ROS levels and overexpressed antioxidant enzymes. The stress conditions resulted in an increase in the number of autophagosomes and exacerbated the expression of different autophagy-related genes (Atgs). A correlation between mitochondrial dysfunction and autophagic phenotypes was also observed. After 24 h, acid stress and nutritional deprivation induced metacyclogenesis phenotypes (mitochondrial remodeling and autophagy). On the other hand, alkaline stress was transient due to insect blood feeding and culminated in an increase in autophagic flux as a survival mechanism.

Keywords:  Trypanosoma cruzi; autophagy; mitochondria; nutritional deprivation; pH stress

DOI:  https://doi.org/10.1016/j.bbadis.2020.166028
J Immunother Cancer. 2020 Dec;pii: e001372. [Epub ahead of print]8(2):

Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles.

An Ning Cheng, Li-Chun Cheng, Cheng-Liang Kuo, Yu Kang Lo, Han-Yu Chou, Chung-Hsing Chen, Yi-Hao Wang, Tsung-Hsien Chuang, Shih-Jung Cheng, Alan Yueh-Luen Lee.

  BACKGROUND: Mitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).METHODS: We explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.
RESULTS: We found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.
CONCLUSIONS: The levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.

Keywords:  inflammation; interferon inducers; tumor biomarkers; tumor escape; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2020-001372
Semin Immunol. 2020 Nov 30. pii: S1044-5323(20)30051-8. [Epub ahead of print] 101435

Memory CD8+ T cell responses to cancer.

Jichang Han, Nikhil Khatwani, Tyler G Searles, Mary Jo Turk, Christina V Angeles.

  Long-lived memory CD8+ T cells play important roles in tumor immunity. Studies over the past two decades have identified four subsets of memory CD8+ T cells - central, effector, stem-like, and tissue resident memory - that either circulate through blood, lymphoid and peripheral organs, or reside in tissues where cancers develop. In this article, we will review studies from both pre-clinical mouse models and human patients to summarize the phenotype, distribution and unique features of each memory subset, and highlight specific roles of each subset in anti-tumor immunity. Moreover, we will discuss how stem-cell like and resident memory CD8+ T cell subsets relate to exhausted tumor-infiltrating lymphocytes (TIL) populations. These studies reveal how memory CD8+ T cell subsets together orchestrate durable immunity to cancer.

Keywords:  Central memory (T(CM)); Effector memory (T(EM)); Exhaustion; Resident memory (T(RM)); Stem cell memory (T(SCM)); Tumor immunity

DOI:  https://doi.org/10.1016/j.smim.2020.101435