bims-imseme 2022-02-06 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–02–06
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Ionic mitigation of CD4+ T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc.
Autophagy takes it all - autophagy inducers target immune aging.
Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors.
The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.
Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity.
Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8+ T cells.
Immunostimulatory effects of vitamin B5 improve anticancer immunotherapy.
CAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells.
Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.
PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer.
Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.
Cutting Edge: l-Arginine Transfer from Antigen-Presenting Cells Sustains CD4+ T Cell Viability and Proliferation.
T Cell Responses to the Microbiota.

Sci Rep. 2022 Feb 04. 12(1): 1943

Ionic mitigation of CD4+ T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc.

Anna Krone, Yan Fu, Simon Schreiber, Johanna Kotrba, Loisa Borde, Aileen Nötzold, Christoph Thurm, Jonas Negele, Tobias Franz, Sabine Stegemann-Koniszewski, Jens Schreiber, Christoph Garbers, Aniruddh Shukla, Robert Geffers, Burkhart Schraven, Dirk Reinhold, Anne Dudeck, Annegret Reinhold, Andreas J Müller, Sascha Kahlfuss.

T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells. The essential trace element zinc has reported immunomodulatory capacity and high zinc concentrations interfere with T cell function. However, how high doses of zinc affect T cell gene networks and metabolism remained so far elusive. Herein, we demonstrate by means of transcriptomic analysis that zinc aspartate (UNIZINK), a registered pharmaceutical infusion solution with high bioavailability, negatively regulates gene networks controlling DNA replication and the energy metabolism of murine CD3/CD28-activated CD4+ T cells. Specifically, in the presence of zinc, CD4+ T cells show impaired expression of cell cycle, glycolytic and tricarboxylic acid cycle genes, which functionally cumulates in reduced glycolysis, oxidative phosphorylation, metabolic fitness and viability. Moreover, high zinc concentrations impaired nuclear expression of the metabolic transcription factor MYC, prevented Th1 and Th2 differentiation in vitro and reduced Th1 autoimmune central nervous system (CNS) inflammation and Th2 asthmatic airway inflammation induced by house dust mites in vivo. Together, we find that higher zinc doses impair the metabolic fitness of CD4+ T cells and prevent Th1 CNS autoimmunity and Th2 allergy.

DOI: https://doi.org/10.1038/s41598-022-04827-6
Dis Model Mech. 2022 01 01. pii: dmm049345. [Epub ahead of print]15(1):

Autophagy takes it all - autophagy inducers target immune aging.

Heidi Zinecker, Anna Katharina Simon.

  Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.

Keywords:  Aging; Autophagy; Autophagy inducer; Immune system

DOI:  https://doi.org/10.1242/dmm.049345
J Immunother Cancer. 2022 Feb;pii: e003958. [Epub ahead of print]10(2):

Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors.

Yosuke Dotsu, Daisuk Muraoka, Naohisa Ogo, Yudai Sonoda, Kiyoshi Yasui, Hiroyuki Yamaguchi, Hideo Yagita, Hiroshi Mukae, Akira Asai, Hiroaki Ikeda.

   BACKGROUND: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy.
METHODS: We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis.
RESULTS: PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells.
CONCLUSIONS: These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells.

Keywords:  CD8-positive T-lymphocytes; lymphocytes; metabolic networks and pathways; tumor-infiltrating

DOI:  https://doi.org/10.1136/jitc-2021-003958
Nat Immunol. 2022 Feb;23(2): 287-302

The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.

Axel R Concepcion, Larry E Wagner, Jingjie Zhu, Anthony Y Tao, Jun Yang, Alireza Khodadadi-Jamayran, Yin-Hu Wang, Menghan Liu, Rebecca E Rose, Drew R Jones, William A Coetzee, David I Yule, Stefan Feske.

The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production-a phenotype associated with downmodulation of p53 signaling. Mechanistically, LRRC8C mediates the transport of 2'3'cGAMP in T cells, resulting in STING and p53 activation. Inhibition of STING recapitulates the phenotype of LRRC8C-deficient T cells, whereas overexpression of p53 inhibits their enhanced T cell function. Lrrc8c-/- mice have exacerbated T cell-dependent immune responses, including immunity to influenza A virus infection and experimental autoimmune encephalomyelitis. Our results identify cGAMP uptake through LRRC8C and STING-p53 signaling as a new inhibitory signaling pathway in T cells and adaptive immunity.

DOI: https://doi.org/10.1038/s41590-021-01105-x
J Clin Invest. 2022 Feb 01. pii: e153604. [Epub ahead of print]132(3):

Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity.

Zhenhua Ren, Anli Zhang, Zhichen Sun, Yong Liang, Jianfeng Ye, Jian Qiao, Bo Li, Yang-Xin Fu.

  PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.

Keywords:  Cancer immunotherapy; Immunology

DOI:  https://doi.org/10.1172/JCI153604
Sci Adv. 2022 Feb 04. 8(5): eabl9783

Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8+ T cells.

Jugal Kishore Das, Yijie Ren, Anil Kumar, Hao-Yun Peng, Liqing Wang, Xiaofang Xiong, Robert C Alaniz, Paul de Figueiredo, Xingcong Ren, Xiaoqi Liu, Alexey G Ryazonov, Jin-Ming Yang, Jianxun Song.

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8+ T cells. CD8+ T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8+ T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8+ T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8+ T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8+ T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8+ T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.

DOI: https://doi.org/10.1126/sciadv.abl9783
Oncoimmunology. 2022 ;11(1): 2031500

Immunostimulatory effects of vitamin B5 improve anticancer immunotherapy.

Melanie Bourgin, Oliver Kepp, Guido Kroemer.

  Vitamin B5 (panthotenic acid), the precursor of coenzyme A (CoA), is contained in most food items and is produced by the intestinal microbiota. A recent study published in Cell Metabolism reports that vitamin B5 and CoA favor the differentiation of CD8+ cytotoxic T cells into interleukin-22 (IL-22)-producing Tc22 cells, likely through fueling mitochondrial metabolism. Importantly, in a small cohort of melanoma patients, the plasma levels of vitamin B5 positively correlate with responses to PD-1-targeted immunotherapy. Moreover, in mice, supplementation with vitamin B5 increases the efficacy of PD-L1-targeted cancer immunotherapy, and in vitro culture of T cells with CoA enhances their antitumor activity upon adoptive transfer into mice. These finding suggest that vitamin B5 is yet another B vitamin that stimulates anti-cancer immunosurveillance.

Keywords:  Acetyl coenzyme A; immune checkpoint inhibitor; microbiome; nicotinamide; vitamin B3

DOI:  https://doi.org/10.1080/2162402X.2022.2031500
Nat Commun. 2022 Jan 31. 13(1): 587

CAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells.

Nikhil Hebbar, Rebecca Epperly, Abishek Vaidya, Unmesha Thanekar, Sarah E Moore, Masayuki Umeda, Jing Ma, Sagar L Patil, Deanna Langfitt, Sujuan Huang, Cheng Cheng, Jeffery M Klco, Stephen Gottschalk, M Paulina Velasquez.

Developing CAR T cells for acute myeloid leukemia (AML) has been hampered by a paucity of targets that are expressed on AML blasts and not on hematopoietic progenitor cells (HPCs). Here we demonstrate that GRP78 is expressed on the cell surface of primary AML blasts but not HPCs. To target GRP78, we generate T cell expressing a GRP78-specific peptide-based CAR, which show evidence of minimal fratricide post activation/transduction and antigen-dependent T cell differentiation. GRP78-CAR T cells recognize and kill GRP78-positive AML cells without toxicity to HPCs. In vivo, GRP78-CAR T cells have significant anti-AML activity. To prevent antigen-dependent T cell differentiation, we block CAR signaling and GRP78 cell surface expression post activation by using dasatinib during GRP78-CAR T cell manufacturing. This significantly improves their effector function in vitro and in vivo. Thus, targeting cell surface GRP78-positive AML with CAR T cells is feasible, and warrants further active exploration.

DOI: https://doi.org/10.1038/s41467-022-28243-6
Cell Rep. 2022 Feb 01. pii: S2211-1247(22)00031-6. [Epub ahead of print]38(5): 110320

Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.

Rebecca L Westbrook, Esther Bridges, Jennie Roberts, Cristina Escribano-Gonzalez, Katherine L Eales, Lisa A Vettore, Paul D Walker, Elias Vera-Siguenza, Himani Rana, Federica Cuozzo, Kattri-Liis Eskla, Hans Vellama, Abeer Shaaban, Colin Nixon, Hendrik Luuk, Gareth G Lavery, David J Hodson, Adrian L Harris, Daniel A Tennant.

  The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.

Keywords:  NADH; PYCR1; cancer; hypoxia; mitochondria; proline; redox

DOI:  https://doi.org/10.1016/j.celrep.2022.110320
Nat Cancer. 2020 Jul;1(7): 681-691

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer.

Soyoung A Oh, Dai-Chen Wu, Jeanne Cheung, Armando Navarro, Huizhong Xiong, Rafael Cubas, Klara Totpal, Henry Chiu, Yan Wu, Laetitia Comps-Agrar, Andrew M Leader, Miriam Merad, Merone Roose-Germa, Soren Warming, Minhong Yan, Jeong M Kim, Sascha Rutz, Ira Mellman.

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.

DOI: https://doi.org/10.1038/s43018-020-0075-x
Nature. 2022 Feb 02.

Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.

J Joseph Melenhorst, Gregory M Chen, Meng Wang, David L Porter, Changya Chen, McKensie A Collins, Peng Gao, Shovik Bandyopadhyay, Hongxing Sun, Ziran Zhao, Stefan Lundh, Iulian Pruteanu-Malinici, Christopher L Nobles, Sayantan Maji, Noelle V Frey, Saar I Gill, Lifeng Tian, Irina Kulikovskaya, Minnal Gupta, David E Ambrose, Megan M Davis, Joseph A Fraietta, Jennifer L Brogdon, Regina M Young, Anne Chew, Bruce L Levine, Donald L Siegel, Cécile Alanio, E John Wherry, Frederic D Bushman, Simon F Lacey, Kai Tan, Carl H June.

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

DOI: https://doi.org/10.1038/s41586-021-04390-6
J Immunol. 2022 Feb 15. 208(4): 793-798

Cutting Edge: l-Arginine Transfer from Antigen-Presenting Cells Sustains CD4+ T Cell Viability and Proliferation.

Rebecca R Crowther, Stephanie M Schmidt, Shannon M Lange, Melanie C McKell, Michelle C Robillard, Junfang Zhao, Wendy D Haffey, Michael A Wyder, Kenneth D Greis, Kenneth D R Setchell, Joseph E Qualls.

Metabolomics analyses suggest changes in amino acid abundance, particularly l-arginine (L-ARG), occur in patients with tuberculosis. Immune cells require L-ARG to fuel effector functions following infection. We have previously described an L-ARG synthesis pathway in immune cells; however, its role in APCs has yet to be uncovered. Using a coculture system with mycobacterial-specific CD4+ T cells, we show APC L-ARG synthesis supported T cell viability and proliferation, and activated T cells contained APC-derived L-ARG. We hypothesize that APCs supply L-ARG to support T cell activation under nutrient-limiting conditions. This work expands the current model of APC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.

DOI: https://doi.org/10.4049/jimmunol.2100652
Annu Rev Immunol. 2022 Feb 03.

T Cell Responses to the Microbiota.

Ivaylo I Ivanov, Timur Tuganbaev, Ashwin N Skelly, Kenya Honda.

The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-immunol-101320-011829