bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–04–16
fiveteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection.
  2. Immune Profiling Reveals Decreases in Circulating Regulatory and Exhausted T Cells in Human Hypertension.
  3. DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells.
  4. Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.
  5. T cells go with the flow: Aquaporin 4 is required for full T cell activation.
  6. No rest for the wicked: Tumor cell senescence reshapes the immune microenvironment.
  7. Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.
  8. Phosphatidylserine-positive extracellular vesicles boost effector CD8+ T cell responses during viral infection.
  9. Metabolic challenges and interventions in CAR T cell therapy.
  10. Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.
  11. Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
  12. PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial.
  13. Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process.
  14. Metabolism in type 2 immune responses.
  15. Advances in cancer immunotherapies.
  1. J Virol. 2023 Apr 11. e0022523
    Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection.
    Julia M DeRogatis, Emily N Neubert, Karla M Viramontes, Monique L Henriquez, Dequina A Nicholas, Roberto Tinoco.
      Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.
    Keywords:  CD38; CD8+ T cell; LCMV; T cell exhaustion; T cells; chronic viral infection; effector T cell; metabolism
    DOI:  https://doi.org/10.1128/jvi.00225-23
  2. JACC Basic Transl Sci. 2023 Mar;8(3): 319-336
    Immune Profiling Reveals Decreases in Circulating Regulatory and Exhausted T Cells in Human Hypertension.
    Matthew R Alexander, Bethany L Dale, Charles D Smart, Fernando Elijovich, Cara E Wogsland, Sierra M Lima, Jonathan M Irish, Meena S Madhur.
      Evidence from nonhuman animal models demonstrates an important role for immune cells in hypertension, but immune cell changes in human hypertension are less clear. Using mass cytometry, we demonstrate novel and selective reductions in CCR10+ regulatory T cells (Tregs) and PD-1+CD57-CD8+ memory T cells. RNA sequencing reveals that CCR10+ Tregs exhibit gene expression changes consistent with enhanced immunosuppressive function. In addition, CITE-Seq demonstrates that PD-1+CD57-CD8+ memory T cells exhibit features of T-cell exhaustion. Taken together, these results provide novel evidence for decreases in anti-inflammatory and/or hypofunctional T-cell populations that may contribute to enhanced inflammation in human hypertension.
    Keywords:  hypertension; immunity; inflammation; lymphocytes; mass cytometry
    DOI:  https://doi.org/10.1016/j.jacbts.2022.09.007
  3. Immunity. 2023 Apr 05. pii: S1074-7613(23)00137-1. [Epub ahead of print]
    DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells.
    Sara Quon, Bingfei Yu, Brendan E Russ, Kirill Tsyganov, Hongtuyet Nguyen, Clara Toma, Maximilian Heeg, James D Hocker, J Justin Milner, Shane Crotty, Matthew E Pipkin, Stephen J Turner, Ananda W Goldrath.
      Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.
    Keywords:  CD8(+) T cell; CTCF; Hi-C; enhancer; epigenetics; genome organization; promoter
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.017
  4. Cancer Cell. 2023 Apr 12. pii: S1535-6108(23)00087-9. [Epub ahead of print]
    Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.
    Cem Sievers, Marco Craveiro, Jay Friedman, Yvette Robbins, Xinping Yang, Ke Bai, Andy Nguyen, Jason M Redman, Raj Chari, Patrick Soon-Shiong, Jeffrey Schlom, James Gulley, Clint T Allen.
      Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8+ T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.
    Keywords:  TGF-β; glutamine metabolism; neoadjuvant immunotherapy; neoepitope-specific T cells; single-cell transcriptomics; tissue-resident T cells
    DOI:  https://doi.org/10.1016/j.ccell.2023.03.014
  5. J Leukoc Biol. 2023 Apr 12. pii: qiad041. [Epub ahead of print]
    T cells go with the flow: Aquaporin 4 is required for full T cell activation.
    Sharon Celeste Morley.
      
    Keywords:  Cells: T Lymphocytes; Molecules: Signaling Cascade; Molecules: T Cell Receptors/Receptor Complex; Process: Cell Activation; Process: T Cell Responses
    DOI:  https://doi.org/10.1093/jleuko/qiad041
  6. Cancer Cell. 2023 Mar 29. pii: S1535-6108(23)00086-7. [Epub ahead of print]
    No rest for the wicked: Tumor cell senescence reshapes the immune microenvironment.
    Ann Hanna, Justin M Balko.
      Senescence induces key phenotypic changes that can modulate immune responses. Four recent publications in Cancer Discovery, Nature, and Nature Cancer highlight how senescent cells (aged normal or chemotherapy-treated cells) express antigen presentation machinery, present antigens, and interact with T cells and dendritic cells to robustly activate the immune system and promote anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.ccell.2023.03.013
  7. Nat Commun. 2023 Apr 12. 14(1): 2087
    Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.
    Kateryna Onyshchenko, Ren Luo, Elena Guffart, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Niedermann.
      Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8+ T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8+ T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8+ T cells increase. Consistent with the surge in tumor-specific CD8+ T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8+ T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.
    DOI:  https://doi.org/10.1038/s41467-023-37825-x
  8. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2210047120
    Phosphatidylserine-positive extracellular vesicles boost effector CD8+ T cell responses during viral infection.
    Lisa Rausch, Lavinia Flaskamp, Ashretha Ashokkumar, Anne Trefzer, Christine Ried, Veit R Buchholz, Reinhard Obst, Tobias Straub, Thomas Brocker, Jan Kranich.
      CD8+ T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine+ (PS) extracellular vesicles (EVs). These EVs interact especially with CD8+ T cells; however, it remains unclear whether they can actively modulate CD8+ T cell responses. In this study, we have developed a method to analyze cell-bound PS+ EVs and their target cells in vivo. We show that EV+ cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8+ T cells. Superresolution imaging revealed that PS+ EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8+ T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS+ EVs provide Ag-specific adjuvant effects to activated CD8+ T cells in vivo.
    Keywords:  CD8 T cells; LCMV; exosomes; extracellular vesicles; phosphatidylserine
    DOI:  https://doi.org/10.1073/pnas.2210047120
  9. Sci Immunol. 2023 Apr 14. 8(82): eabq3016
    Metabolic challenges and interventions in CAR T cell therapy.
    Jhan-Jie Peng, Limei Wang, Zhiyu Li, Cheng-Lung Ku, Ping-Chih Ho.
      Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.
    DOI:  https://doi.org/10.1126/sciimmunol.abq3016
  10. Leukemia. 2023 Apr 08.
    Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.
    Xiaoguang Wang, Canping Chen, Dan Vuong, Sonia Rodriguez-Rodriguez, Vi Lam, Carly Roleder, Jing H Wang, Swetha Kambhampati, Allison Berger, Nathan Pennock, Pallawi Torka, Francisco Hernandez-Ilizaliturri, Tanya Siddiqi, Lili Wang, Zheng Xia, Alexey V Danilov.
      Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.
    DOI:  https://doi.org/10.1038/s41375-023-01889-x
  11. Nat Commun. 2023 Apr 10. 14(1): 2018
    Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
    Pradeep Ramalingam, Michael C Gutkin, Michael G Poulos, Taylor Tillery, Chelsea Doughty, Agatha Winiarski, Ana G Freire, Shahin Rafii, David Redmond, Jason M Butler.
      Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels. We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.
    DOI:  https://doi.org/10.1038/s41467-023-37783-4
  12. Nat Cancer. 2023 Apr 10.
    PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial.
    Leonie Voorwerk, Olga I Isaeva, Hugo M Horlings, Sara Balduzzi, Maksim Chelushkin, Noor A M Bakker, Elisa Champanhet, Hannah Garner, Karolina Sikorska, Claudette E Loo, Inge Kemper, Ingrid A M Mandjes, Michiel de Maaker, Jasper J L van Geel, Jorianne Boers, Maaike de Boer, Roberto Salgado, Marloes G J van Dongen, Gabe S Sonke, Karin E de Visser, Ton N Schumacher, Christian U Blank, Lodewyk F A Wessels, Agnes Jager, Vivianne C G Tjan-Heijnen, Carolien P Schröder, Sabine C Linn, Marleen Kok.
      Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial ( NCT03147040 ), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml-1 min-1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.
    DOI:  https://doi.org/10.1038/s43018-023-00542-x
  13. Ageing Res Rev. 2023 Apr 07. pii: S1568-1637(23)00087-9. [Epub ahead of print]87 101928
    Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process.
    Antero Salminen.
      Circadian clocks control the internal sleep-wake rhythmicity of 24 h which is synchronized by the solar cycle. Circadian regulation of metabolism evolved about 2.5 billion years ago, i.e., the rhythmicity has been conserved from cyanobacteria and Archaea through to mammals although the mechanisms utilized have developed with evolution. While the aryl hydrocarbon receptor (AhR) is an evolutionarily conserved defence mechanism against environmental threats, it has gained many novel functions during evolution, such as the regulation of cell cycle, proteostasis, and many immune functions. There is robust evidence that AhR signaling impairs circadian rhythmicity, e.g., by interacting with the core BMAL1/CLOCK complex and disturbing the epigenetic regulation of clock genes. The maintenance of circadian rhythms is impaired with aging, disturbing metabolism and many important functions in aged organisms. Interestingly, it is known that AhR signaling promotes an age-related tissue degeneration, e.g., it is able to inhibit autophagy, enhance cellular senescence, and disrupt extracellular matrix. These alterations are rather similar to those induced by a long-term impairment of circadian rhythms. However, it is not known whether AhR signaling enhances the aging process by impairing circadian homeostasis. I will examine the experimental evidence indicating that AhR signaling is able to promote the age-related degeneration via a disruption of circadian rhythmicity.
    Keywords:  Ageing; IDO1; Immunosuppression; Kynurenine; Lifespan; Longevity
    DOI:  https://doi.org/10.1016/j.arr.2023.101928
  14. Immunity. 2023 Apr 11. pii: S1074-7613(23)00127-9. [Epub ahead of print]56(4): 723-741
    Metabolism in type 2 immune responses.
    Agnieszka M Kabat, Erika L Pearce, Edward J Pearce.
      The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.007
  15. Cell. 2023 Apr 13. pii: S0092-8674(23)00217-9. [Epub ahead of print]186(8): 1814-1814.e1
    Advances in cancer immunotherapies.
    Oula K Dagher, Robert D Schwab, Shawna K Brookens, Avery D Posey.
      Therapeutic modalities that engage the immune system to recognize and eliminate cancer, known as cancer immunotherapy, has emerged as a distinct pillar of cancer therapy. Among the most promising treatment approaches are therapeutic vaccines, immune checkpoint blockade, bispecific T-cell engagers (BiTEs) and adoptive cell therapies. These approaches share a common mechanism of action, which is elicitation of a T-cell-based immune response, either endogenous or engineered, against tumor antigens, but interactions between the innate immune system, particularly antigen-presenting cells, and immune effectors also underlie the efficacy of cancer immunotherapies and approaches engaging these cells are also under development. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2023.02.039
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