bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–07–09
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T-cell Cholesterol Accumulation, Aging, and Atherosclerosis.
  2. Hierarchical transcriptional network governing heterogeneous T cell exhaustion and its implications for immune checkpoint blockade.
  3. Taurine levels modulate aging.
  4. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
  5. S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8+ T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma.
  6. Diet, nutrient supply, and tumor immune responses.
  7. IL-7 producing immunotherapy improves ex vivo T cell functions of immunosenescent patients, especially post hip fracture.
  8. Determination of CAR T cell metabolism in an optimized protocol.
  9. T cell receptor signaling strength establishes the chemotactic properties of effector CD8+ T cells that control tissue-residency.
  10. Spatial mapping of cellular senescence: emerging challenges and opportunities.
  11. Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20.
  12. Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.
  13. Pannexin 1 regulates CD8+ T cell function and memory formation.
  14. Sicilian semi- and supercentenarians: identification of age-related T cell immunophenotype to define longevity trait.
  15. SUSD2-IL-2 receptor interaction hinders antitumoral CD8+ T-cell activity: Implications for cancer immunotherapy.
  16. Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment.
  17. An Improved Method to Isolate Mitochondrial Contact Sites.
  18. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation.
  19. Mitochondrial ROS-dependent CD4+PD-1+T cells are pathological expansion in patients with primary immune thrombocytopenia.
  20. HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway.
  21. Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.
  22. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.
  1. Curr Atheroscler Rep. 2023 Jul 03.
    T-cell Cholesterol Accumulation, Aging, and Atherosclerosis.
    Venetia Bazioti, Benedek Halmos, Marit Westerterp.
       PURPOSE OF REVIEW: The majority of leukocytes in advanced human atherosclerotic plaques are T-cells. T-cell subsets exert pro- or anti-atherogenic effects largely via the cytokines they secrete. Tregulatory cells (Tregs) are anti-inflammatory, but may lose these properties during atherosclerosis, proposed to be downstream of cholesterol accumulation. Aged T-cells also accumulate cholesterol. The effects of T-cell cholesterol accumulation on T-cell fate and atherosclerosis are not uniform.
    RECENT FINDINGS: T-cell cholesterol accumulation enhances differentiation into pro-atherogenic cytotoxic T-cells and boosts their killing capacity, depending on the localization and extent of cholesterol accumulation. Excessive cholesterol accumulation induces T-cell exhaustion or T-cell apoptosis, the latter decreasing atherosclerosis but impairing T-cell functionality in terms of killing capacity and proliferation. This may explain the compromised T-cell functionality in aged T-cells and T-cells from CVD patients. The extent of T-cell cholesterol accumulation and its cellular localization determine T-cell fate and downstream effects on atherosclerosis and T-cell functionality.
    Keywords:  ABC transporters; Atherosclerosis; CVD; Cholesterol; T-cell
    DOI:  https://doi.org/10.1007/s11883-023-01125-y
  2. Front Immunol. 2023 ;14 1198551
    Hierarchical transcriptional network governing heterogeneous T cell exhaustion and its implications for immune checkpoint blockade.
    Weihong Tian, Gaofeng Qin, Miaomiao Jia, Wuhao Li, Weili Cai, Hui Wang, Yangjing Zhao, Xuanwen Bao, Wangzhi Wei, Yu Zhang, Qixiang Shao.
      The fundamental principle of immune checkpoint blockade (ICB) is to protect tumor-infiltrating T cells from being exhausted. Despite the remarkable success achieved by ICB treatment, only a small group of patients benefit from it. Characterized by a hypofunctional state with the expression of multiple inhibitory receptors, exhausted T (Tex) cells are a major obstacle in improving ICB. T cell exhaustion is a progressive process which adapts to persistent antigen stimulation in chronic infections and cancers. In this review, we elucidate the heterogeneity of Tex cells and offer new insights into the hierarchical transcriptional regulation of T cell exhaustion. Factors and signaling pathways that induce and promote exhaustion are also summarized. Moreover, we review the epigenetic and metabolic alterations of Tex cells and discuss how PD-1 signaling affects the balance between T cell activation and exhaustion, aiming to provide more therapeutic targets for applications of combinational immunotherapies.
    Keywords:  PD-1; T cell exhaustion; T cell factor 1; TOX; chronic TCR stimulation; heterogeneous; immune checkpoint blockade
    DOI:  https://doi.org/10.3389/fimmu.2023.1198551
  3. Nat Aging. 2023 Jul 06.
    Taurine levels modulate aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00465-3
  4. Nature. 2023 Jul 05.
    SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
    Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, Hongbo Chi.
      Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.
    DOI:  https://doi.org/10.1038/s41586-023-06299-8
  5. Adv Sci (Weinh). 2023 Jul 06. e2300110
    S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8+ T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma.
    Huihuang Li, Jinbo Chen, Zhenghao Li, Minfeng Chen, Zhenyu Ou, Miao Mo, Ruizhe Wang, Shiyu Tong, Peihua Liu, Zhiyong Cai, Chunyu Zhang, Zhi Liu, Dingshan Deng, Jinhui Liu, Chunliang Cheng, Jiao Hu, Xiongbing Zu.
      Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8+ T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8+ T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8+ T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5+ tumor cells and CD8+ T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8+ T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.
    Keywords:  S100 family; bladder carcinoma; effector immune cells; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202300110
  6. Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00104-8. [Epub ahead of print]
    Diet, nutrient supply, and tumor immune responses.
    Claire L McIntyre, Ayantu Temesgen, Lydia Lynch.
      Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies.
    Keywords:  T cells; cancer; diet; immune cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.trecan.2023.06.003
  7. Hum Vaccin Immunother. 2023 Aug 01. 19(2): 2232247
    IL-7 producing immunotherapy improves ex vivo T cell functions of immunosenescent patients, especially post hip fracture.
    Chrystel Marton, Alix Minaud, Charles-Antoine Coupet, Manon Chauvin, Jamila Dhiab, Hélène Vallet, Jacques Boddaert, Nadine Kehrer, Bérangère Bastien, Geneviève Inchauspe, Luc Barraud, Delphine Sauce.
      Following acute stress such as trauma or sepsis, most of critically ill elderly patients become immunosuppressed and susceptible to secondary infections and enhanced mortality. We have developed a virus-based immunotherapy encoding human interleukin-7 (hIL-7) aiming at restoring both innate an adaptative immune homeostasis in these patients. We assessed the impact of this encoded hIL-7 on the ex vivo immune functions of T cells from PBMC of immunosenescent patients with or without hip fracture. T-cell ex vivo phenotyping was characterized in terms of senescence (CD57), IL-7 receptor (CD127) expression, and T cell differentiation profile. Then, post stimulation, activation status, and functionality (STAT5/STAT1 phosphorylation and T cell proliferation assays) were evaluated by flow cytometry. Our data show that T cells from both groups display immunosenescence features, express CD127 and are activated after stimulation by virotherapy-produced hIL-7-Fc. Interestingly, hip fracture patients exhibit a unique functional ability: An important T cell proliferation occurred compared to controls following stimulation with hIL-7-Fc. In addition, stimulation led to an increased naïve T cell as well as a decreased effector memory T cell proportions compared to controls. This preliminary study indicates that the produced hIL-7-Fc is well recognized by T cells and initiates IL-7 signaling through STAT5 and STAT1 phosphorylation. This signaling efficiently leads to T cell proliferation and activation and enables a T cell "rejuvenation." These results are in favor of the clinical development of the hIL-7-Fc expressing virotherapy to restore or induce immune T cell responses in immunosenescent hip fracture patients.
    Keywords:  Immunosenescence; T-cell functions; cytokine; hip fracture; immunosuppression; immunotherapy; interleukin-7; trauma; virotherapy
    DOI:  https://doi.org/10.1080/21645515.2023.2232247
  8. Front Bioeng Biotechnol. 2023 ;11 1207576
    Determination of CAR T cell metabolism in an optimized protocol.
    Sandy Joaquina, Christopher Forcados, Benjamin Caulier, Else Marit Inderberg, Sébastien Wälchli.
      Adoptive transfer of T cells modified to express chimeric antigenic receptors (CAR) has emerged as a solution to cure refractory malignancies. However, although CAR T cell treatment of haematological cancers has now shown impressive improvement in outcome, solid tumours have been more challenging to control. The latter type is protected by a strong tumour microenvironment (TME) which might impact cellular therapeutic treatments. Indeed, the milieu around the tumour can become particularly inhibitory to T cells by directly affecting their metabolism. Consequently, the therapeutic cells become physically impeded before being able to attack the tumour. It is therefore extremely important to understand the mechanism behind this metabolic break in order to develop TME-resistant CAR T cells. Historically, the measurement of cellular metabolism has been performed at a low throughput which only permitted a limited number of measurements. However, this has been changed by the introduction of real-time technologies which have lately become more popular to study CAR T cell quality. Unfortunately, the published protocols lack uniformity and their interpretation become confusing. We herein tested the essential parameters to perform a metabolic study on CAR T cells and propose a check list of factors that should be set in order to draw sound conclusion.
    Keywords:  CAR T cell; Seahorse XF96; cancer therapy; immunotherapy; metabolim
    DOI:  https://doi.org/10.3389/fbioe.2023.1207576
  9. Nat Commun. 2023 07 04. 14(1): 3928
    T cell receptor signaling strength establishes the chemotactic properties of effector CD8+ T cells that control tissue-residency.
    Mahmoud Abdelbary, Samuel J Hobbs, James S Gibbs, Jonathan W Yewdell, Jeffrey C Nolz.
      Tissue-resident memory (TRM) CD8+ T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of TRM differentiation within tissue microenvironments remain unresolved. Here, using an IFNγ-YFP reporter system to identify CD8+ T cells executing antigen-dependent effector functions, we define the transcriptional consequences and functional mechanisms controlled by TCR-signaling strength that occur within the skin during viral infection to promote TRM differentiation. TCR-signaling both enhances CXCR6-mediated migration and suppresses migration toward sphingosine-1-phosphate, indicating the programming of a 'chemotactic switch' following secondary antigen encounter within non-lymphoid tissues. Blimp1 was identified as the critical target of TCR re-stimulation that is necessary to establish this chemotactic switch and for TRM differentiation to efficiently occur. Collectively, our findings show that access to antigen presentation and strength of TCR-signaling required for Blimp1 expression establishes the chemotactic properties of effector CD8+ T cells to promote residency within non-lymphoid tissues.
    DOI:  https://doi.org/10.1038/s41467-023-39592-1
  10. Nat Aging. 2023 Jul 03.
    Spatial mapping of cellular senescence: emerging challenges and opportunities.
    Aditi U Gurkar, Akos A Gerencser, Ana L Mora, Andrew C Nelson, Anru R Zhang, Anthony B Lagnado, Archibald Enninful, Christopher Benz, David Furman, Delphine Beaulieu, Diana Jurk, Elizabeth L Thompson, Fei Wu, Fernanda Rodriguez, Grant Barthel, Hao Chen, Hemali Phatnani, Indra Heckenbach, Jeffrey H Chuang, Jeremy Horrell, Joana Petrescu, Jonathan K Alder, Jun Hee Lee, Laura J Niedernhofer, Manoj Kumar, Melanie Königshoff, Marta Bueno, Miiko Sokka, Morten Scheibye-Knudsen, Nicola Neretti, Oliver Eickelberg, Peter D Adams, Qianjiang Hu, Quan Zhu, Rebecca A Porritt, Runze Dong, Samuel Peters, Stella Victorelli, Thomas Pengo, Timur Khaliullin, Vidyani Suryadevara, Xiaonan Fu, Ziv Bar-Joseph, Zhicheng Ji, João F Passos.
      Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-023-00446-6
  11. Life Sci Alliance. 2023 Sep;pii: e202201683. [Epub ahead of print]6(9):
    Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20.
    Nicholas K Preiss, Yasmin Kamal, Owen M Wilkins, Chenyang Li, Fred W Kolling, Heidi W Trask, Young-Kwang Usherwood, Chao Cheng, Hildreth R Frost, Edward J Usherwood.
      Members of the BTB-ZF transcription factor family regulate the immune system. Our laboratory identified that family member Zbtb20 contributes to the differentiation, recall responses, and metabolism of CD8 T cells. Here, we report a characterization of the transcriptional and epigenetic signatures controlled by Zbtb20 at single-cell resolution during the effector and memory phases of the CD8 T cell response. Without Zbtb20, transcriptional programs associated with memory CD8 T cell formation were up-regulated throughout the CD8 T response. A signature of open chromatin was associated with genes controlling T cell activation, consistent with the known impact on differentiation. In addition, memory CD8 T cells lacking Zbtb20 were characterized by open chromatin regions with overrepresentation of AP-1 transcription factor motifs and elevated RNA- and protein-level expressions of the corresponding AP-1 components. Finally, we describe motifs and genomic annotations from the DNA targets of Zbtb20 in CD8 T cells identified by cleavage under targets and release under nuclease (CUT&RUN). Together, these data establish the transcriptional and epigenetic networks contributing to the control of CD8 T cell responses by Zbtb20.
    DOI:  https://doi.org/10.26508/lsa.202201683
  12. Commun Biol. 2023 Jul 07. 6(1): 696
    Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.
    You-Yuan Wang, Cheng Zhen, Wei Hu, Hui-Huang Huang, Yan-Jun Li, Ming-Ju Zhou, Jing Li, Yu-Long Fu, Peng Zhang, Xiao-Yu Li, Tao Yang, Jin-Wen Song, Xing Fan, Jun Zou, Si-Run Meng, Ya-Qin Qin, Yan-Mei Jiao, Ruonan Xu, Ji-Yuan Zhang, Chun-Bao Zhou, Jin-Hong Yuan, Lei Huang, Ming Shi, Liang Cheng, Fu-Sheng Wang, Chao Zhang.
      CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.
    DOI:  https://doi.org/10.1038/s42003-023-04975-z
  13. Nat Rev Immunol. 2023 Jul 03.
    Pannexin 1 regulates CD8+ T cell function and memory formation.
    Mireia Cruz De Los Santos, Andreas Lundqvist.
      
    DOI:  https://doi.org/10.1038/s41577-023-00913-6
  14. Clin Exp Immunol. 2023 Jul 03. pii: uxad074. [Epub ahead of print]
    Sicilian semi- and supercentenarians: identification of age-related T cell immunophenotype to define longevity trait.
    Mattia Emanuela Ligotti, Giulia Accardi, Anna Aiello, Stefano Aprile, Anna Calabrò, Rosalia Caldarella, Calogero Caruso, Marcello Ciaccio, Anna Maria Corsale, Francesco Dieli, Marta Di Simone, Giovanni Maurizio Giammanco, Chiara Mascarella, Arne N Akbar, Serena Meraviglia, Giuseppina Candore.
      The immunophenotype of oldest centenarians, i.e., semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T effector memory cells re-expressing CD45RA (TEMRA), according to their Cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not attributable to a single contributor, but should be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones.
    Keywords:  CMV; immune ageing; immunophenotype; longevity; semi-supercentenarians; supercentenarians
    DOI:  https://doi.org/10.1093/cei/uxad074
  15. Allergy. 2023 Jul 04.
    SUSD2-IL-2 receptor interaction hinders antitumoral CD8+ T-cell activity: Implications for cancer immunotherapy.
    Pilar M Moreno-Sanchez, Andrea Scafidi, Ilaria Salvato.
      
    Keywords:  CAR T cells; CD8+ T cells; IL-2; SUSD2; cancer immunotherapy
    DOI:  https://doi.org/10.1111/all.15804
  16. Front Immunol. 2023 ;14 1204363
    Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment.
    Qianting Guan, Meiwen Han, Qinghao Guo, Fangfei Yan, Ming Wang, Qin Ning, Dong Xi.
      CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.
    Keywords:  cytokine therapy; epigenetic therapy; exhausted CD8 + T cells; immune checkpoint blockade; metabolism-based therapy; transcription factor-based therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1204363
  17. J Vis Exp. 2023 06 16.
    An Improved Method to Isolate Mitochondrial Contact Sites.
    Siavash Khosravi, Johanna Frickel, Max E Harner.
      Mitochondria are present in virtually all eukaryotic cells and perform essential functions that go far beyond energy production, for instance, the synthesis of iron-sulfur clusters, lipids, or proteins, Ca2+ buffering, and the induction of apoptosis. Likewise, mitochondrial dysfunction results in severe human diseases such as cancer, diabetes, and neurodegeneration. In order to perform these functions, mitochondria have to communicate with the rest of the cell across their envelope, which consists of two membranes. Therefore, these two membranes have to interact constantly. Proteinaceous contact sites between the mitochondrial inner and outer membranes are essential in this respect. So far, several contact sites have been identified. In the method described here, Saccharomyces cerevisiae mitochondria are used to isolate contact sites and, thus, identify candidates that qualify for contact site proteins. We used this method to identify the mitochondrial contact site and cristae organizing system (MICOS) complex, one of the major contact site-forming complexes in the mitochondrial inner membrane, which is conserved from yeast to humans. Recently, we further improved this method to identify a novel contact site consisting of Cqd1 and the Por1-Om14 complex.
    DOI:  https://doi.org/10.3791/65444
  18. Front Immunol. 2023 ;14 1117092
    IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation.
    Junghwa Lee, Kyungmin Lee, Hyeonjin Bae, Kunhee Lee, Solhwi Lee, Junhui Ma, Kyungjo Jo, Ijun Kim, ByulA Jee, Minyong Kang, Se Jin Im.
      In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed increased expression of ribosome-related genes and decreased expression of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.
    Keywords:  IL-15; cancer; chronic viral infection; maintenance; progenitor exhausted CD8 T cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1117092
  19. Int Immunopharmacol. 2023 Jul 04. pii: S1567-5769(23)00922-0. [Epub ahead of print]122 110597
    Mitochondrial ROS-dependent CD4+PD-1+T cells are pathological expansion in patients with primary immune thrombocytopenia.
    Weiping Li, Ziran Bai, Jiaqing Liu, Yawei Tang, Chunlai Yin, Minli Jin, Lijun Mu, Xia Li.
       OBJECTIVE: Aberrant-activated T cells, especially CD4+T cells, play a crucial part in the pathogenetic progress of immune thrombocytopenia (ITP). PD-1-mediated signals play a negative part in the activation of CD4+T cells. However, knowledge is limited on the pathogenic characteristics and function of CD4+PD-1+T cells in ITP.
    MATERIALS AND METHODS: The frequency and phenotype including cell activation, apoptosis, and cytokine production of CD4+PD-1+T cells were evaluated by flow cytometry. PD-1 Ligation Assay was performed to assess the function of PD-1 pathway in CD4+T cells. Mitochondrial reactive oxygen species (mtROS) were detected by MitoSOX Red probe.
    RESULTS: Compared with healthy controls (HC), the frequencies of CD4+PD-1+T cells were significantly increased in ITP patients. However, these cells are not exhausted despite PD-1 expression. Besides retaining cytokine-producing potential, these CD4+PD-1+T cells also had a possible B-cell helper function including expressing ICOS, CD84, and CD40L. Moreover, the CD4+PD-1+T cell subset contained higher levels of mitochondrial ROS than CD4+PD-1-T cell subset in patients with ITP. And mtROS inhibition could reduce the secretion of the inflammatory cytokines and regulate the function of CD4+PD-1+T cells. Upon in-vitro T cell receptor (TCR) stimulation of CD4+T cells in the presence of plate-bound PD-L1 fusion protein (PD-L1-Ig), CD4+T cells from ITP patients appeared resistant to such PD-1-mediated inhibition of interferon (IFN)-γ secretion.
    CONCLUSIONS: The CD4+PD-1+T cells were more abundant in patients with ITP. Additionally, this CD4+PD-1+T cell subset may be a potential etiology of ITP and a potential immune therapeutic target for ITP patients in the future.
    Keywords:  CD4(+)T cell; Immune thrombocytopenia (ITP); Mitochondrial reactive oxygen species (mtROS); PD-1
    DOI:  https://doi.org/10.1016/j.intimp.2023.110597
  20. Cell Rep. 2023 Jul 01. pii: S2211-1247(23)00742-8. [Epub ahead of print]42(7): 112731
    HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway.
    Bai-Yu Li, Wan-Qiu Peng, Yang Liu, Liang Guo, Qi-Qun Tang.
      Energy-dissipating adipocytes have the potential to improve metabolic health. Here, we identify hypoxia-induced gene domain protein-1a (HIGD1A), a mitochondrial inner membrane protein, as a positive regulator of adipose browning. HIGD1A is induced in thermogenic fats by cold exposure. Peroxisome proliferator-activated receptor gamma (PPARγ) transactivates HIGD1A expression synergistically with peroxisome proliferators-activated receptor γ coactivator α (PGC1α). HIGD1A knockdown inhibits adipocyte browning, whereas HIGD1A upregulation promotes the browning process. Mechanistically, HIGD1A deficiency impairs mitochondrial respiration to increase reactive oxygen species (ROS) level. This increases NAD+ consumption for DNA damage repair and curtails the NAD+/NADH ratio, which inhibits sirtuin1 (SIRT1) activity, thereby compromising adipocyte browning. Conversely, overexpression of HIGD1A blunts the above process to promote adaptive thermogenesis. Furthermore, mice with HIGD1A knockdown in inguinal and brown fat have impaired thermogenesis and are prone to diet-induced obesity (DIO). Overexpression of HIGD1A favors adipose tissue browning, ultimately preventing DIO and metabolic disorders. Thus, the mitochondrial protein HIGD1A links SIRT1 activity to adipocyte browning by inhibiting ROS levels.
    Keywords:  CP: Metabolism; DNA damage; HIGD1A; NAD(+)/NADH ratio; ROS; SIRT1; adipocyte browning; hypoxia-induced gene domain protein-1a; sirtuin1
    DOI:  https://doi.org/10.1016/j.celrep.2023.112731
  21. Cell Death Dis. 2023 Jul 06. 14(7): 403
    Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis.
    Luisa Ricci, Federico Uchenna Stanley, Tanja Eberhart, Francesco Mainini, David Sumpton, Simone Cardaci.
      Succinate dehydrogenase (SDH) is the mitochondrial enzyme converting succinate to fumarate in the tricarboxylic acid (TCA) cycle. SDH acts as a tumor suppressor with germline loss-of-function mutations in its encoding genes predisposing to aggressive familial neuroendocrine and renal cancer syndromes. Lack of SDH activity disrupts the TCA cycle, imposes Warburg-like bioenergetic features, and commits cells to rely on pyruvate carboxylation for anabolic needs. However, the spectrum of metabolic adaptations enabling SDH-deficient tumors to cope with a dysfunctional TCA cycle remains largely unresolved. By using previously characterized Sdhb-deleted kidney mouse cells, here we found that SDH deficiency commits cells to rely on mitochondrial glutamate-pyruvate transaminase (GPT2) activity for proliferation. We showed that GPT2-dependent alanine biosynthesis is crucial to sustain reductive carboxylation of glutamine, thereby circumventing the TCA cycle truncation determined by SDH loss. By driving the reductive TCA cycle anaplerosis, GPT2 activity fuels a metabolic circuit maintaining a favorable intracellular NAD+ pool to enable glycolysis, thus meeting the energetic demands of SDH-deficient cells. As a metabolic syllogism, SDH deficiency confers sensitivity to NAD+ depletion achieved by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway. Beyond identifying an epistatic functional relationship between two metabolic genes in the control of SDH-deficient cell fitness, this study disclosed a metabolic strategy to increase the sensitivity of tumors to interventions limiting NAD availability.
    DOI:  https://doi.org/10.1038/s41419-023-05927-5
  22. Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00735-0. [Epub ahead of print]42(7): 112724
    The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.
    Julia Katharina Charlotte Kreß, Christina Jessen, Anita Hufnagel, Werner Schmitz, Thamara Nishida Xavier da Silva, Ancély Ferreira Dos Santos, Laura Mosteo, Colin R Goding, José Pedro Friedmann Angeli, Svenja Meierjohann.
      The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
    Keywords:  ATF4; CHAC1; CP: Cell biology; GSH; NRF2; SLC7A11; integrated stress response; melanoma
    DOI:  https://doi.org/10.1016/j.celrep.2023.112724
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