bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒10‒23
nine papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. A BDNF-TrkB autocrine loop enhances senescent cell viability.
  2. Characterization of age-related immune features after autologous NK cell infusion: Protocol for an open-label and randomized controlled trial.
  3. Taurine enhances the antitumor efficacy of PD-1 antibody by boosting CD8+ T cell function.
  4. Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components.
  5. An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposi's sarcoma under ART.
  6. SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.
  7. The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy.
  8. Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment.
  9. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics.
  1. Nat Commun. 2022 Oct 20. 13(1): 6228
    A BDNF-TrkB autocrine loop enhances senescent cell viability.
    Carlos Anerillas, Allison B Herman, Rachel Munk, Amanda Garrido, Kwan-Wood Gabriel Lam, Matthew J Payea, Martina Rossi, Dimitrios Tsitsipatis, Jennifer L Martindale, Yulan Piao, Krystyna Mazan-Mamczarz, Jinshui Fan, Chang-Yi Cui, Supriyo De, Kotb Abdelmohsen, Rafael de Cabo, Myriam Gorospe.
      Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
    DOI:  https://doi.org/10.1038/s41467-022-33709-8
  2. Front Immunol. 2022 ;13 940577
    Characterization of age-related immune features after autologous NK cell infusion: Protocol for an open-label and randomized controlled trial.
    Xiaofeng Tang, Biaolong Deng, Aiping Zang, Xiaowen He, Ye Zhou, Daimeng Wang, Dan Li, Xueyu Dai, Jieqiong Chen, Xuhua Zhang, Ye Liu, Yonghua Xu, Jingjing Chen, Weijie Zheng, Luding Zhang, Constance Gao, Huanfeng Yang, Bin Li, Xueqi Wang.
      Background: Aging is usually accompanied by functional declines of the immune system, especially in T-cell responses. However, little is known about ways to alleviate this.Methods: Here, 37 middle-aged healthy participants were recruited, among which 32 were intravenously administrated with expanded NK cells and 5 with normal saline. Then, we monitored changes of peripheral senescent and exhausted T cells within 4 weeks after infusion by flow cytometry, as well as serum levels of senescence-associated secretory phenotype (SASP)-related factors. In vitro co-culture assays were performed to study NK-mediated cytotoxic activity against senescent or exhausted T cells. Functional and phenotypic alteration of NK cells before and after expansion was finally characterized.
    Results: After NK cell infusion, senescent CD28-, CD57+, CD28-CD57+, and CD28-KLRG1+ CD4+ and CD8+ T-cell populations decreased significantly, so did PD-1+ and TIM-3+ T cells. These changes were continuously observed for 4 weeks. Nevertheless, no significant changes were observed in the normal saline group. Moreover, SASP-related factors including IL-6, IL-8, IL-1α, IL-17, MIP-1α, MIP-1β, and MMP1 were significantly decreased after NK cell infusion. Further co-culture assays showed that expanded NK cells specifically and dramatically eliminated senescent CD4+ T cells other than CD28+CD4+ T cells. They also showed improved cytotoxic activity, with different expression patterns of activating and inhibitory receptors including NKG2C, NKG2A, KLRG1, LAG3, CD57, and TIM3.
    Conclusion: Our findings imply that T-cell senescence and exhaustion is a reversible process in healthy individuals, and autologous NK cell administration can be introduced to alleviate the aging.
    Clinical Trial Registration: ClinicalTrials.gov, ChiCTR-OOh-17011878.
    Keywords:  SASP; T-cell exhaustion; T-cell senescence; aging; natural killer cells
    DOI:  https://doi.org/10.3389/fimmu.2022.940577
  3. Cancer Immunol Immunother. 2022 Oct 20.
    Taurine enhances the antitumor efficacy of PD-1 antibody by boosting CD8+ T cell function.
    Yu Ping, Jiqi Shan, Yaqing Liu, Fengsen Liu, Liuya Wang, Zhangnan Liu, Jieyao Li, Dongli Yue, Liping Wang, Xinfeng Chen, Yi Zhang.
      The functional state of CD8+ T cells determines the therapeutic efficacy of PD-1 blockade antibodies in tumors. Amino acids are key nutrients for maintaining T cell antitumor immunity. In this study, we used samples from lung cancer patients treated with PD-1 blockade antibodies to assay the amino acids in their serum by mass spectrometry. We found that lung cancer patients with high serum taurine levels generally responded to PD-1 blockade antibody therapy, in parallel with the secretion of high levels of cytotoxic cytokines (IFN-γ and TNF-α). CD8+ T cells cultured with exogenous taurine exhibited decreased apoptosis, enhanced proliferation, and increased secretion of cytotoxic cytokines. High SLC6A6 expression in CD8+ T cells was positively associated with an effector T cell signature. SLC6A6 knockdown limited the function and proliferation of CD8+ T cells. RNA sequencing revealed that SLC6A6 knockdown altered the calcium signaling pathway, oxidative phosphorylation, and T cell receptor signaling in CD8+ T cells. Furthermore, taurine enhanced T cell proliferation and function in vitro by stimulation of PLCγ1-mediated calcium and MAPK signaling. Taurine plus immune checkpoint blockade antibody significantly attenuated tumor growth and markedly improved the function and proliferation of CD8+ T cells in a mouse tumor model. Thus, our findings indicate that taurine is an important driver for improving CD8+ T cell immune responses and could serve as a potential therapeutic agent for cancer patients.
    Keywords:  Antitumor immunity; CD8+ T cell; Calcium signaling; MAPK signaling; PD-1 blockade antibody; Taurine
    DOI:  https://doi.org/10.1007/s00262-022-03308-z
  4. Biogerontology. 2022 Oct 19.
    Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components.
    Rohit Sharma, Bhawna Diwan, Anamika Sharma, Jacek M Witkowski.
      Immunological aging is strongly associated with the observable deleterious effects of human aging. Our understanding of the causes, effects, and therapeutics of aging immune cells has long been considered within the sole purview of immunosenescence. However, it is being progressively realized that immunosenescence may not be the only determinant of immunological aging. The cellular senescence-centric theory of aging proposes a more fundamental and specific role of immune cells in regulating senescent cell (SC) burden in aging tissues that has augmented the notion of senescence immunotherapy. Now, in addition, several emerging studies are suggesting that cellular senescence itself may be prevalent in aging immune cells, and that senescent immune cells exhibiting characteristic markers of cellular senescence, similar to non-leucocyte cells, could be among the key drivers of various facets of physiological aging. The present review integrates the current knowledge related to immunosenescence and cellular senescence in immune cells per se, and aims at providing a cohesive overview of these two phenomena and their significance in immunity and aging. We present evidence and rationalize that understanding the extent and impact of cellular senescence in immune cells vis-à-vis immunosenescence is necessary for truly comprehending the notion of an 'aged immune cell'. In addition, we also discuss the emerging significance of dietary factors such as phytochemicals, probiotic bacteria, fatty acids, and micronutrients as possible modulators of immunosenescence and cellular senescence. Evidence and opportunities related to nutritional bioactive components and immunological aging have been deliberated to augment potential nutrition-oriented immunotherapy during aging.
    Keywords:  Aging; Cellular senescence; Immunity; Immunosenescence; Inflamm-aging; Nutrition
    DOI:  https://doi.org/10.1007/s10522-022-09995-6
  5. Front Cell Dev Biol. 2022 ;10 961021
    An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposi's sarcoma under ART.
    Genevieve T Clutton, Ann Marie K Weideman, Nilu P Goonetilleke, Toby Maurer.
      HIV-associated Kaposi's sarcoma (KS), which is caused by Kaposi's sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally occurs in individuals with durable HIV viral suppression and CD4 T cell recovery under antiretroviral therapy (ART). The underlying mechanisms associated with this phenomenon are unclear. Suppression of viral infections can be mediated by CD8 T cells, which detect infected cells via their T cell receptor and the CD8 coreceptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 ("CD8dim T cells") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial alterations (PGC-1α, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS disease under ART. CD8 coreceptor down-modulation may be symptomatic of ongoing disease.
    Keywords:  CD8 coreceptor; HIV; KSHV; Kaposi’s sarcoma; T cells; metabolism; mitochondria; senescence
    DOI:  https://doi.org/10.3389/fcell.2022.961021
  6. Nat Immunol. 2022 Oct 20.
    SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.
    Bao Zhao, Weipeng Gong, Anjun Ma, Jianwen Chen, Maria Velegraki, Hong Dong, Zihao Liu, Lingling Wang, Tamio Okimoto, Devin M Jones, Yu L Lei, Meixiao Long, Kenneth J Oestreich, Qin Ma, Gang Xin, David P Carbone, Kai He, Zihai Li, Haitao Wen.
      Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8+ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4+ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.
    DOI:  https://doi.org/10.1038/s41590-022-01326-8
  7. Int J Hematol. 2022 Oct 21.
    The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy.
    Ying Wang, Tien Bui, Yi Zhang.
      EZH2 is a histone methyltransferase. It catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3) to control gene transcription critical for cell proliferation, differentiation, expansion, and function. For instance, EZH2 plays a central role in regulating T-cell immune responses. EZH2 restrains terminal differentiation of effector CD8 T cells, promotes formation of precursor and mature memory CD8 T cells, regulates appropriate lineage-specification and identity maintenance of helper CD4 T cells, and maintains survival of differentiated antigen-specific T cells. Most importantly, EZH2 is shown to be important for reinvigoration of exhausted chimeric antigen receptor (CAR) T cells. Dysregulated EZH2 function has been linked to many forms of cancer, including lymphomas and solid tumors. In B-cell lymphoid malignancies, EZH2 is overexpressed to drive tumorigenesis. These specific effects of EZH2, in the context of its roles in catalyzing H3K27me3 and orchestrating gene transcription programs in both normal and malignant cells, establishes EZH2 as a unique target for drug development. Here, we will discuss Ezh2 regulation of T-cell immunity, EZH2-mediated lymphomagenesis, and therapeutic benefits of EZH2 inhibitors to the treatment of lymphoma.
    Keywords:  EZH2; Epigenetics; Lymphoma; Precision therapy; T cells; Tumor immunotherapy
    DOI:  https://doi.org/10.1007/s12185-022-03466-x
  8. Front Immunol. 2022 ;13 940052
    Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment.
    Bayley R McRitchie, Billur Akkaya.
      The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals' genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+ T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+ T cells and CD8+ T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+ T cells and CD8+ T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
    Keywords:  T cell exhaustion; Treg, mechanism; immunotherapy; regulatory T cell; tumor
    DOI:  https://doi.org/10.3389/fimmu.2022.940052
  9. Nat Immunol. 2022 Oct 21.
    Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics.
    Josephine R Giles, Shin Foong Ngiow, Sasikanth Manne, Amy E Baxter, Omar Khan, Ping Wang, Ryan Staupe, Mohamed S Abdel-Hakeem, Hua Huang, Divij Mathew, Mark M Painter, Jennifer E Wu, Yinghui Jane Huang, Rishi R Goel, Patrick K Yan, Giorgos C Karakousis, Xiaowei Xu, Tara C Mitchell, Alexander C Huang, E John Wherry.
      Naïve CD8+ T cells can differentiate into effector (Teff), memory (Tmem) or exhausted (Tex) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within Teff, Tmem and Tex populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of Tex cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1+ stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of Tex subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the Tex population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8+ T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.
    DOI:  https://doi.org/10.1038/s41590-022-01338-4
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