bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒04‒23
seventeen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.
  2. The metabolic cross-talk between cancer and T cells.
  3. Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis.
  4. ITK signaling regulates a switch between T helper 17 and T regulatory cell lineages via a calcium-mediated pathway.
  5. A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.
  6. The histone demethylase Utx controls CD8+ T-cell-dependent antitumor immunity via epigenetic regulation of the effector function.
  7. Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8+ T cells.
  8. Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells.
  9. Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.
  10. Maintenance and recall of memory T cell populations against tuberculosis: Implications for vaccine design.
  11. The relationship between CD4+ T cell glycolysis and their functions.
  12. Mitochondrial GTP Metabolism Regulates Reproductive Aging.
  13. Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response.
  14. Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.
  15. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.
  16. ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors.
  17. Impact of aging on immune function in the pathogenesis of pulmonary diseases: Potential for therapeutic targets.
  1. bioRxiv. 2023 Apr 04. pii: 2023.04.03.533021. [Epub ahead of print]
    Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.
    Aliya Lakhani, Ximin Chen, Laurence C Chen, Mobina Khericha, Yvonne Y Chen, Junyoung O Park.
      Metabolism is an indispensable part of T-cell proliferation, activation, and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are comprised of extracellular domains that determine cancer specificity, often using single-chain variable fragments (scFvs), and intracellular domains that trigger signaling upon antigen binding. Here we show that CARs differing only in the scFv reprogram T-cell metabolism differently. Even in the absence of antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observe basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harboring rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14g2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Since CAR-dependent metabolic reprogramming alters cellular energetics, nutrient utilization, and proliferation, metabolic profiling should be an integral part of CAR-T cell development.
    DOI:  https://doi.org/10.1101/2023.04.03.533021
  2. Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]
    The metabolic cross-talk between cancer and T cells.
    Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.
      The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.
    Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tibs.2023.03.004
  3. Cell Rep Med. 2023 Apr 18. pii: S2666-3791(23)00122-2. [Epub ahead of print]4(4): 101012
    Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis.
    Shozo Ohtsuki, Chenyao Wang, Ryu Watanabe, Hui Zhang, Mitsuhiro Akiyama, Melanie C Bois, Joseph J Maleszewski, Kenneth J Warrington, Gerald J Berry, Jörg J Goronzy, Cornelia M Weyand.
      Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.
    Keywords:  CD155; CD96; ER stress; IL-9; T cell; autoimmune vasculitis; autoimmunity; giant cell arteritis; immune checkpoint receptors; macrophage
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101012
  4. bioRxiv. 2023 Apr 03. pii: 2023.04.01.535229. [Epub ahead of print]
    ITK signaling regulates a switch between T helper 17 and T regulatory cell lineages via a calcium-mediated pathway.
    Orchi Anannya, Weishan Huang, Avery August.
      The balance of pro-inflammatory T helper type 17 (Th17) and anti-inflammatory T regulatory (Treg) cells is crucial in maintaining immune homeostasis in health and disease conditions. Differentiation of naïve CD4 + T cells into Th17/Treg cells is dependent upon T cell receptor (TCR) activation and cytokine signaling, which includes the kinase ITK. Signals from ITK can regulate the differentiation of Th17 and Treg cell fate choice, however, the mechanism remains to be fully understood. We report here that in the absence of ITK activity, instead of developing into Th17 cells under Th17 conditions, naïve CD4 + T cells switch to cells expressing the Treg marker Foxp3 (Forkhead box P3). These switched Foxp3 + Treg like cells retain suppressive function and resemble differentiated induced Tregs in their transcriptomic profile, although their chromatin accessibility profiles are intermediate between Th17 and induced Tregs cells. Generation of the switched Foxp3 + Treg like cells was associated with reduced expression of molecules involved in mitochondrial oxidative phosphorylation and glycolysis, with reduced activation of the mTOR signaling pathway, and reduced expression of BATF. This ITK dependent switch between Th17 and Treg cells was reversed by increasing intracellular calcium. These findings suggest potential strategies for fine tune the TCR signal strength via ITK to regulate the balance of Th17/Treg cells.
    DOI:  https://doi.org/10.1101/2023.04.01.535229
  5. Nat Biomed Eng. 2023 Apr 17.
    A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.
    Patrick Reichenbach, Greta Maria Paola Giordano Attianese, Khaoula Ouchen, Elisabetta Cribioli, Melanie Triboulet, Sarah Ash, Margaux Saillard, Romain Vuillefroy de Silly, George Coukos, Melita Irving.
      Vectors that facilitate the engineering of T cells that can better harness endogenous immunity and overcome suppressive barriers in the tumour microenvironment would help improve the safety and efficacy of T-cell therapies for more patients. Here we report the design, production and applicability of T-cell engineering of a lentiviral vector leveraging an antisense configuration and comprising a promoter driving the constitutive expression of a tumour-directed receptor and a second promoter enabling the efficient activation-inducible expression of a genetic payload. The vector allows for the delivery of a variety of genes to human T cells, as we show for interleukin-2 and a microRNA-based short hairpin RNA for the knockdown of the gene coding for haematopoietic progenitor kinase 1, a negative regulator of T-cell-receptor signalling. We also show that a gene encoded under an activation-inducible promoter is specifically expressed by tumour-redirected T cells on encountering a target antigen in the tumour microenvironment. The single two-gene-encoding vector can be produced at high titres under an optimized protocol adaptable to good manufacturing practices.
    DOI:  https://doi.org/10.1038/s41551-023-01013-5
  6. Cancer Sci. 2023 Apr 17.
    The histone demethylase Utx controls CD8+ T-cell-dependent antitumor immunity via epigenetic regulation of the effector function.
    Haruna Noda, Junpei Suzuki, Yuko Matsuoka, Akira Matsumoto, Makoto Kuwahara, Yoshiaki Kamei, Yasutsugu Takada, Masakatsu Yamashita.
      CD8+ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8+ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8+ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8+ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8+ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8+ T cells to tumor sites, was substantially decreased in Utx KO CD8+ T cells. These findings suggest that Utx promotes CD8+ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.
    Keywords:   Utx ; CD8+ T cell; Cxcr3; antitumor immunity; histone H3K27
    DOI:  https://doi.org/10.1111/cas.15814
  7. Res Sq. 2023 Apr 05. pii: rs.3.rs-2196637. [Epub ahead of print]
    Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8+ T cells.
    Anita Chong, Jared Pollard, Grace Hynes, Dengping Yin, Malay Mandal, Fotini Gounari, Maria-Luisa Alegre.
      Alloreactive memory T cells, unlike naive T cells, fail to be restrained by transplantation tolerance protocols or regulatory T cells, and therefore represent a critical barrier to long-term graft acceptance. Using female mice sensitized by rejection of fully-mismatched paternal skin allografts, we show that subsequent semi-allogeneic pregnancy successfully reprograms memory fetus/graft-specific CD8+ T cells (T FGS ) towards hypofunction in a manner that is mechanistically distinct from naive T FGS . Post-partum memory TFGS were durably hypofunctional, exhibiting enhanced susceptibility to transplantation tolerance induction. Furthermore, multi-omics studies revealed that pregnancy induced extensive phenotypic and transcriptional modifications in memory T FGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory T FGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive T FGS . These data reveal a novel link between T cell memory and hypofunction via exhaustion circuits and pregnancy-mediated epigenetic imprinting. This conceptual advance has immediate clinical relevance to pregnancy and transplantation tolerance.
    DOI:  https://doi.org/10.21203/rs.3.rs-2196637/v1
  8. Nat Immunol. 2023 Apr 20.
    Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells.
    Jesus Corria-Osorio, Santiago J Carmona, Evangelos Stefanidis, Massimo Andreatta, Yaquelin Ortiz-Miranda, Tania Muller, Ioanna A Rota, Isaac Crespo, Bili Seijo, Wilson Castro, Cristina Jimenez-Luna, Leonardo Scarpellino, Catherine Ronet, Aodrenn Spill, Evripidis Lanitis, Pedro Romero, Sanjiv A Luther, Melita Irving, George Coukos.
      To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
    DOI:  https://doi.org/10.1038/s41590-023-01477-2
  9. Geroscience. 2023 Apr 22.
    Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.
    Cheryl Zi Jin Phua, Xiaqing Zhao, Lesly Turcios-Hernandez, Morrigan McKernan, Morteza Abyadeh, Siming Ma, Daniel Promislow, Matt Kaeberlein, Alaattin Kaya.
      Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain's proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.
    Keywords:  Aging; Metabolism; Mitochondrial proteins; Omics; Yeast
    DOI:  https://doi.org/10.1007/s11357-023-00796-4
  10. Front Immunol. 2023 ;14 1100741
    Maintenance and recall of memory T cell populations against tuberculosis: Implications for vaccine design.
    Xin Liu, Haoran Li, Shanshan Li, Jinfeng Yuan, Yu Pang.
      Despite the widespread use of standardised drug regimens, advanced diagnostics, and Mycobacterium bovis Bacille-Calmette-Guérin (BCG) vaccines, the global tuberculosis (TB) epidemic remains uncontrollable. To address this challenge, improved vaccines are urgently required that can elicit persistent immunologic memory, the hallmark of successful vaccines. Nonetheless, the processes underlying the induction and maintenance of immunologic memory are not entirely understood. Clarifying how memory T cells (Tm cells) are created and survive long term may be a crucial step towards the development of effective T cell-targeted vaccines. Here, we review research findings on the memory T cell response, which involves mobilization of several distinct Tm cell subsets that are required for efficient host suppression of M. tuberculosis (Mtb) activity. We also summaries current knowledge related to the T cell response-based host barrier against Mtb infection and discuss advantages and disadvantages of novel TB vaccine candidates.
    Keywords:  Mycobacterium tuberculosis; host immune responses; memory T cells; tuberculosis; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2023.1100741
  11. Trends Endocrinol Metab. 2023 Apr 14. pii: S1043-2760(23)00059-0. [Epub ahead of print]
    The relationship between CD4+ T cell glycolysis and their functions.
    Siyi Liu, Shan Liao, Lin Liang, Jun Deng, Yanhong Zhou.
      CD4+ T cells are effector T cells (Teffs) produced by the differentiation of initial T cells in peripheral lymphoid tissue after being attacked by antigens, and have an indispensable role in the development and activation of B cells and CD8+ T cells to regulate and assist immunity. In this review, we provide a new perspective on the relationship between CD4+ T cell glycolysis and its function. We summarize the effects of changes in the glycolysis level of CD4+ T cells on their activation, differentiation, proliferation, and survival. In addition, we emphasize that regulation of the glycolysis level of CD4+ T cells changes their inflammatory phenotypes and function. The study of immune metabolism has received more attention recently, but more work is needed to answer many open questions.
    Keywords:  CD4(+) T cell; differentiation; function; glycolysis; proliferation
    DOI:  https://doi.org/10.1016/j.tem.2023.03.006
  12. bioRxiv. 2023 Apr 03. pii: 2023.04.02.535296. [Epub ahead of print]
    Mitochondrial GTP Metabolism Regulates Reproductive Aging.
    Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica Sowa, Jue D Wang, Meng C Wang.
      Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS), promotes reproductive longevity in Caenorhabditis elegans. We further revealed an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by the GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mitochondrial GTP and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mitochondrial GTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and reveal mitochondrial fission induction as an effective strategy to improve reproductive health.
    DOI:  https://doi.org/10.1101/2023.04.02.535296
  13. bioRxiv. 2023 Apr 06. pii: 2023.04.04.535379. [Epub ahead of print]
    Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response.
    Jonathan H Chen, Linda T Nieman, Maxwell Spurrell, Vjola Jorgji, Peter Richieri, Katherine H Xu, Roopa Madhu, Milan Parikh, Izabella Zamora, Arnav Mehta, Christopher S Nabel, Samuel S Freeman, Joshua D Pirl, Chenyue Lu, Catherine B Meador, Jaimie L Barth, Mustafa Sakhi, Alexander L Tang, Siranush Sarkizova, Colles Price, Nicolas F Fernandez, George Emanuel, Jiang He, Katrina Van Raay, Jason W Reeves, Keren Yizhak, Matan Hofree, Angela Shih, Moshe Sade-Feldman, Genevieve M Boland, Karin Pelka, Martin Aryee, Ilya Korsunsky, Mari Mino-Kenudson, Justin F Gainor, Nir Hacohen.
      The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11 + macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7 + LAMP3 + dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
    DOI:  https://doi.org/10.1101/2023.04.04.535379
  14. Res Sq. 2023 Apr 04. pii: rs.3.rs-2736771. [Epub ahead of print]
    Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.
    Juan Young, Hong-Jai Park, Minhyung Kim, Jennefer Par-Young, Hugh Bartlett, Hye Sun Kim, Serhan Unlu, Lais Osmani, Min Sun Shin, Richard Bucala, Christopher van Dyck, Heather Allore, Adam Mecca, Sungyong You, Insoo Kang.
      CD45RA + effector memory (EM) CD8 + T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα) low EM CD8 + T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rα low aging genes). Here we investigated whether IL-7Rα low aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ra low aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rα low aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rα low aging gene signature with AD.
    DOI:  https://doi.org/10.21203/rs.3.rs-2736771/v1
  15. Science. 2023 Apr 21. 380(6642): eabj5559
    Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.
    Nazma Malik, Bibiana I Ferreira, Pablo E Hollstein, Stephanie D Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S Shadel, Uri Manor, Reuben J Shaw.
      Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.
    DOI:  https://doi.org/10.1126/science.abj5559
  16. Nat Immunol. 2023 Apr 17.
    ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors.
    Yeonsun Hong, Brandon L Walling, Hye-Ran Kim, William S Serratelli, John R Lozada, Cooper J Sailer, Andrea M Amitrano, Kihong Lim, Raj Kumar Mongre, Kyun-Do Kim, Tara Capece, Elena B Lomakina, Nicholas S Reilly, Kevin Vo, Scott A Gerber, Tan-Chi Fan, Alice Lin-Tsing Yu, Patrick W Oakes, Richard E Waugh, Chang-Duk Jun, Patrick M Reagan, Minsoo Kim.
      Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8+ T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of βII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1-βII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-023-01498-x
  17. Expert Rev Respir Med. 2023 Apr 20.
    Impact of aging on immune function in the pathogenesis of pulmonary diseases: Potential for therapeutic targets.
    Sadiya Bi Shaikh, Chiara Goracci, Ariel Tjitropranoto, Irfan Rahman.
      INTRODUCTION: Several immunological alterations that occur during pulmonary diseases often mimic alterations observed in the aged lung. From the molecular perspective, pulmonary diseases and aging partake in familiar mechanisms associated with significant dysregulation of the immune systems. Here, we summarized the findings of how aging alters immunity to respiratory conditions to identify age-impacted pathways and mechanisms that contribute to the development of pulmonary diseases.AREAS COVERED: The current review examines the impact of age-related molecular alterations in the aged immune system during various lung diseases such as COPD, IPF, Asthma and alongside many others that could possibly improve on current therapeutic interventions. Moreover, our increased understanding of this phenomenon may play a primary role in shaping immunomodulatory strategies to boost outcomes in the elderly. Here, the authors presents new insights into the context of lung-related diseases and describe the alterations in the functioning of immune cells during various pulmonary conditions altered with age.
    EXPERT OPINION: The expert opinion provided the concepts on how aging alters immunity during pulmonary conditions, and suggests the associated mechanisms during the development of lung diseases. As a result, it becomes important to comprehend the complex mechanism of aging in the immune lung system.
    Keywords:  Aging; COPD; Cellular senescence; Cytokines; IPF; Immunity; Lymphocytes
    DOI:  https://doi.org/10.1080/17476348.2023.2205127
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