bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–10–08
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mitochondria Dictate Function and Fate of HSCs and T Cells.
  2. Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
  3. The immunology and cell biology of T cell aging.
  4. TSC2 S1365A mutation potently regulates CD8+T cell function and differentiation improving adoptive cellular cancer therapy.
  5. Early initiation of antiretroviral therapy preserves the metabolic function of CD4+ T-cells in subtype C HIV-1 infection.
  6. Stress exhausts T cells.
  7. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.
  8. Stress can be exhausting for T cells.
  9. Progressively enhancing stemness of adoptively transferred T cells with PI3Kδ blockade improves metabolism and anti-tumor immunity.
  10. Bcl-3 regulates T cell function through energy metabolism.
  11. T cell memory revisited using single telomere length analysis.
  12. Turning on anti-tumour T cells via MTAP.
  13. Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.
  14. Stress can be exhausting for T cells.
  15. Immunosenescence and Inflammaging in COVID-19.
  16. The aging tumor metabolic microenvironment.
  17. Selenium regulates T cell differentiation in experimental autoimmune thyroiditis in mice.
  18. Mitochondrial Targeted Interventions for Aging.
  19. Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
  20. High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.
  1. Cancer Immunol Res. 2023 10 04. 11(10): 1303-1313
    Mitochondria Dictate Function and Fate of HSCs and T Cells.
    Yingxi Xu, Yi-Hsuan Chiang, Ping-Chih Ho, Nicola Vannini.
      Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0685
  2. Exp Hematol. 2023 Sep 29. pii: S0301-472X(23)01733-2. [Epub ahead of print]
    Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
    Nazanin Karimnia, James Harris, Shen Y Heazlewood, Benjamin Cao, Susan K Nilsson.
      Aging is accompanied by a gradual decline in the function and regenerative capacity of hematopoietic stem cells (HSCs), which leads to increased susceptibility to blood disorders. Recent studies have highlighted the critical role of metabolic regulation in governing the fate and function of HSCs, and alterations in metabolism play a critical role in the age-related changes observed in HSCs. Metabolic processes including glycolysis, mitochondrial function, nutrient sensing and inflammation, profoundly influence the maintenance, self-renewal and differentiation potential of the HSC pool. This review focuses on the metabolic alterations that occur in HSCs during aging and the systemic factors which contribute to HSC metabolic dysregulation, leading to impaired cellular function and reduced regenerative capacity. We highlight the impact of age-associated changes in oxidative stress, mitochondrial dysfunction, nutrient availability and inflammation on HSC metabolism and function. Targeting metabolic pathways and modulating key regulators of metabolism hold promise for reducing age-related HSC dysregulation, thus maintaining functional potential as a path towards healthy aging. Exploiting these metabolic interventions has the potential to improve hemopoietic recovery, enhance immune function and pave the way for novel therapeutic interventions to combat age-related blood disorders.
    Keywords:  Aging; autophagy; hematopoietic stem cell; metabolism; mitochondria; niche; nutrients
    DOI:  https://doi.org/10.1016/j.exphem.2023.09.006
  3. Semin Immunol. 2023 Sep 28. pii: S1044-5323(23)00134-3. [Epub ahead of print]70 101843
    The immunology and cell biology of T cell aging.
    Jörg J Goronzy, Nan-Ping Weng.
      
    DOI:  https://doi.org/10.1016/j.smim.2023.101843
  4. JCI Insight. 2023 Oct 03. pii: e167829. [Epub ahead of print]
    TSC2 S1365A mutation potently regulates CD8+T cell function and differentiation improving adoptive cellular cancer therapy.
    Chirag H Patel, Yi Dong, Navid Koleini, Xiaoxu Wang, Brittany L Dunkerly-Eyring, Jiayu Wen, Mark J Ranek, Laura M Bartle, Daniel B Henderson, Jason G Sagert, David A Kass, Jonathan D Powell.
      MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show manipulating TSC2 at Ser1365 potently regulates activated but not basal mTORC1 signaling in CD8+ T cells. Unlike non-stimulated TSC2 knockout cells, CD8+ T cells expressing a phospho-silencing mutant TSC2-S1365A (SA) retain normal basal mTORC1 activity. PKC and T-cell Receptor (TCR) stimulation induces TSC2 S1365 phosphorylation and preventing this with the SA mutation markedly increases mTORC1 activation and T-cell effector function. Consequently, SA CD8+ T cells display greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also display enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, CD8+ SA T cells used as adoptive cell therapy display greater anti-tumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhances both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.
    Keywords:  Adaptive immunity; Cancer immunotherapy; Cell Biology; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.167829
  5. J Infect Dis. 2023 Oct 06. pii: jiad432. [Epub ahead of print]
    Early initiation of antiretroviral therapy preserves the metabolic function of CD4+ T-cells in subtype C HIV-1 infection.
    Kewreshini K Naidoo, Andrew J Highton, Omolara O Baiyegunhi, Sindiswa P Bhengu, Krista L Dong, Madeleine J Bunders, Marcus Altfeld, Thumbi Ndung'u.
       BACKGROUND: Immune dysfunction often persists in people living with HIV (PLWH) on antiretroviral therapy (ART), clinically manifesting as HIV-1-associated comorbidities. Early ART initiation may reduce incidence of HIV-1-associated immune dysfunction and comorbidities. Immunometabolism is a critical determinant of functional immunity. We investigated the effect of HIV-1 infection and timing of ART initiation on CD4+ T-cell metabolism and function.
    METHODS: Longitudinal blood samples from PLWH that initiated ART either in hyperacute HIV-1 infection (HHI, before peak viremia) or chronic HIV-1 infection (CHI) were assessed for metabolic and immune functions of CD4+ T-cells. Metabolite uptake and mitochondrial mass (MM) were measured using fluorescent analogues and MitoTracker Green accumulation respectively, and were correlated to CD4+ T-cell effector functions.
    RESULTS: Initiation of ART during HHI prevented dysregulation of glucose uptake by CD4+ T-cells; but glucose uptake was reduced pre- and post-ART initiation in CHI. Glucose uptake positively correlated with IL-2 and TNF-⍺ production by CD4+ T-cells. CHI associated with elevated MM in CD4+ TEM that persisted post-ART and correlated with PD-1 expression.
    CONCLUSION: ART initiation in HHI largely prevented metabolic impairment of CD4+ T-cells. ART initiation in CHI associated with persistently dysregulated immunometabolism of CD4+ T-cells that associated with impaired cellular functions and exhaustion.
    Keywords:  CD4+ T-cells; acute HIV-1 infection; antiretroviral therapy; immune dysfunction; immunometabolism
    DOI:  https://doi.org/10.1093/infdis/jiad432
  6. Sci Signal. 2023 Oct 03. 16(805): eadl0724
    Stress exhausts T cells.
    Amy E Baek.
      Catecholamines associated with stress promote T cell exhaustion through the β1-adrenergic receptor.
    DOI:  https://doi.org/10.1126/scisignal.adl0724
  7. Res Sq. 2023 Sep 21. pii: rs.3.rs-3356477. [Epub ahead of print]
    Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.
    Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.
      TCF1 high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 high central memory-like phenotype and increased responsiveness to PD-1 blockade in vivo . PKM2 KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 13 C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells towards a TCF1 high population, generated a unique transcriptional landscape, enhanced tumor control in mice in combination with PD-1 blockade, and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state amenable to checkpoint blockade.
    DOI:  https://doi.org/10.21203/rs.3.rs-3356477/v1
  8. Nat Rev Immunol. 2023 Oct 02.
    Stress can be exhausting for T cells.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00950-1
  9. Cancer Res. 2023 Oct 06.
    Progressively enhancing stemness of adoptively transferred T cells with PI3Kδ blockade improves metabolism and anti-tumor immunity.
    Guillermo O Rangel Rivera, Connor J Dwyer, Hannah M Knochelmann, Aubrey S Smith, Bülent Arman Aksoy, Anna C Cole, Megan M Wyatt, Soundharya Kumaresan, Jessica E Thaxton, Gregory B Lesinski, Chrystal M Paulos.
      Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf-1 and Lef-1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only TCR- or CAR-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor infiltrating lymphocytes (TILs) and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef-1 and Tcf-1 sustained anti-tumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0801
  10. BMC Immunol. 2023 Oct 04. 24(1): 35
    Bcl-3 regulates T cell function through energy metabolism.
    Hui Liu, Lin Zeng, Mengmeng Pan, Liwenhui Huang, Hanying Li, Mengxia Liu, Xinqing Niu, Chenguang Zhang, Hui Wang.
       BACKGROUND: Bcl-3 is a member of the IκB protein family and an essential modulator of NF-κB activity. It is well established that Bcl-3 is critical for the normal development, survival and differentiation of adaptive immune cells, especially T cells. However, the regulation of immune cell function by Bcl-3 through metabolic pathways has rarely been studied.
    RESULTS: In this study, we explored the role of Bcl-3 in the metabolism and function of T cells via the mTOR pathway. We verified that the proliferation of Bcl-3-deficient Jurkat T cells was inhibited, but their activation was promoted, and Bcl-3 depletion regulated cellular energy metabolism by reducing intracellular ATP and ROS production levels and mitochondrial membrane potential. Bcl-3 also regulates cellular energy metabolism in naive CD4+ T cells. In addition, the knockout of Bcl-3 altered the expression of mTOR, Akt, and Raptor, which are metabolism-related genes, in Jurkat cells.
    CONCLUSIONS: This finding indicates that Bcl-3 may mediate the energy metabolism of T cells through the mTOR pathway, thereby affecting their function. Overall, we provide novel insights into the regulatory role of Bcl-3 in T-cell energy metabolism for the prevention and treatment of immune diseases.
    Keywords:  Bcl-3; Jurkat; Metabolism; T cells
    DOI:  https://doi.org/10.1186/s12865-023-00570-3
  11. Front Immunol. 2023 ;14 1100535
    T cell memory revisited using single telomere length analysis.
    Laureline Roger, Kelly L Miners, Louise Leonard, Julia W Grimstead, David A Price, Duncan M Baird, Kristin Ladell.
      The fundamental basis of T cell memory remains elusive. It is established that antigen stimulation drives clonal proliferation and differentiation, but the relationship between cellular phenotype, replicative history, and longevity, which is likely essential for durable memory, has proven difficult to elucidate. To address these issues, we used conventional markers of differentiation to identify and isolate various subsets of CD8+ memory T cells and measured telomere lengths in these phenotypically defined populations using the most sensitive technique developed to date, namely single telomere length analysis (STELA). Naive cells were excluded on the basis of dual expression of CCR7 and CD45RA. Memory subsets were sorted as CD27+CD45RA+, CD27intCD45RA+, CD27-CD45RA+, CD27+CD45RAint, CD27-CD45RAint, CD27+CD45RA-, and CD27-CD45RA- at >98% purity. The shortest median telomere lengths were detected among subsets that lacked expression of CD45RA, and the longest median telomere lengths were detected among subsets that expressed CD45RA. Longer median telomere lengths were also a feature of subsets that expressed CD27 in compartments defined by the absence or presence of CD45RA. Collectively, these data suggested a disconnect between replicative history and CD8+ memory T cell differentiation, which is classically thought to be a linear process that culminates with revertant expression of CD45RA.
    Keywords:  T cell differentiation; T cell memory; T cell senescence; replicative history; telomere length (TL)
    DOI:  https://doi.org/10.3389/fimmu.2023.1100535
  12. Nat Rev Immunol. 2023 Oct 06.
    Turning on anti-tumour T cells via MTAP.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00953-y
  13. Anal Chem. 2023 Oct 06.
    Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.
    Panpan Chen, Yuhao Han, Lei Wang, Yurong Zheng, Zihan Zhu, Yuan Zhao, Mingqi Zhang, Xiangfeng Chen, Xiao Wang, Chenglong Sun.
      The metabolic cross-talk between tumor and immune cells plays key roles in immune cell function and immune checkpoint blockade therapy. However, the characterization of tumor immunometabolism and its spatiotemporal alterations during immune response in a complex tumor microenvironment is challenging. Here, a 3D tumor-immune cell coculture spheroid model was developed to mimic tumor-immune interactions, combined with mass spectrometry imaging-based spatially resolved metabolomics to visualize tumor immunometabolic alterations during immune response. The inhibition of T cells was simulated by coculturing breast tumor spheroids with Jurkat T cells, and the reactivation of T cells can be monitored through diminishing cancer PD-L1 expressions by berberine. This system enables simultaneously screening and imaging discriminatory metabolites that are altered during T cell-mediated antitumor immune response and characterizing the distributions of berberine and its metabolites in tumor spheroids. We discovered that the transport and catabolism of glutamine were significantly reprogrammed during the antitumor immune response at both metabolite and enzyme levels, corresponding to its indispensable roles in energy metabolism and building new biomass. The combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid visually reveals metabolic interactions between tumor and immune cells and possibly helps decipher the role of immunometabolic alterations in tumor immunotherapy.
    DOI:  https://doi.org/10.1021/acs.analchem.2c05734
  14. Nat Rev Drug Discov. 2023 Oct 02.
    Stress can be exhausting for T cells.
    Kirsty Minton.
      
    Keywords:  Cancer; Immunology; Therapeutics
    DOI:  https://doi.org/10.1038/d41573-023-00157-y
  15. Viral Immunol. 2023 Oct 05.
    Immunosenescence and Inflammaging in COVID-19.
    Faezeh Asghari, Amir Asghary, Naime Majidi Zolbanin, Fatemeh Faraji, Reza Jafari.
      Despite knowledge gaps in understanding the full spectrum of the hyperinflammatory phase caused by SARS-CoV-2, according to the World Health Organization (WHO), COVID-19 is still the leading cause of death worldwide. Susceptible people to severe COVID-19 are those with underlying medical conditions or those with dysregulated and senescence-associated immune responses. As the immune system undergoes aging in the elderly, such drastic changes predispose them to various diseases and affect their responsiveness to infections, as seen in COVID-19. At-risk groups experience poor prognosis in terms of disease recovery. Changes in the quantity and quality of immune cell function have been described in numerous literature sites. Impaired immune cell function along with age-related metabolic changes can lead to features such as hyperinflammatory response, immunosenescence, and inflammaging in COVID-19. Inflammaging is related to the increased activity of the most inflammatory factors and is the main cause of age-related diseases and tissue failure in the elderly. Since hyperinflammation is a common feature of most severe cases of COVID-19, this pathway, which is not fully understood, leads to immunosenescence and inflammaging in some individuals, especially in the elderly and those with comorbidities. In this review, we shed some light on the age-related abnormalities of innate and adaptive immune cells and how hyperinflammatory immune responses contribute to the inflammaging process, leading to clinical deterioration. Further, we provide insights into immunomodulation-based therapeutic approaches, which are potentially important considerations in vaccine design for elderly populations.
    Keywords:  COVID-19; hyperinflammatory phase; immunosenescence; inflammaging
    DOI:  https://doi.org/10.1089/vim.2023.0045
  16. Curr Opin Biotechnol. 2023 Sep 30. pii: S0958-1669(23)00105-2. [Epub ahead of print]84 102995
    The aging tumor metabolic microenvironment.
    Steven E Pilley, Edgar Esparza, Peter J Mullen.
      Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102995
  17. Int Immunopharmacol. 2023 Sep 28. pii: S1567-5769(23)01318-8. [Epub ahead of print]124(Pt B): 110993
    Selenium regulates T cell differentiation in experimental autoimmune thyroiditis in mice.
    Wei Wang, Qi-Lan Jiang, Qin Xu, Yang Zeng, Rui Jiang, Jun Jiang.
      Selenium (Se) is an essential trace element that plays an important role in thyroid physiology. Se supplementation can reduce levels of autoimmune thyroid antibodies, which may be beneficial in Hashimoto's thyroiditis (HT). However, the long-term benefits of Se supplementation for HT patients are controversial and there is no clear clinical evidence to support it, so further basic and clinical research is needed. The effect of Se on immune cells, especially T cells, in autoimmune thyroiditis (AIT) has not been elucidated. Here, we replicated a mouse model of experimental autoimmune thyroiditis (EAT) on a high-iodine diet and treated it with Se supplementation. At week 8 of the experiment, Se supplementation reduced the destruction of thyroid follicles and the infiltration rate of lymphocytes in EAT mice, and reversed the disturbance of peripheral blood thyroxine and thyroid autoantibody levels. Further examination revealed that Se had broad effects on T-cell subsets. Its effects include reducing the production of pro-inflammatory cytokines by Th1 cells, inhibiting the differentiation and production of cytokines by Th2 and Th17 cells, and upregulating the differentiation and production of cytokines by Treg cells. These changes help alleviate thyroid follicle damage during EAT. In conclusion, selenium supplementation has the potential to improve the prognosis of AIT by altering the subset differentiation and/or function of CD4+ T cells.
    Keywords:  Experimental autoimmune thyroiditis (EAT); Hashimoto's thyroiditis; NOD/ShiLtJ mouse; Selenium; T cell differentiation
    DOI:  https://doi.org/10.1016/j.intimp.2023.110993
  18. Cold Spring Harb Perspect Med. 2023 Oct 03. pii: a041199. [Epub ahead of print]
    Mitochondrial Targeted Interventions for Aging.
    Sophia Z Liu, Ying Ann Chiao, Peter S Rabinovitch, David J Marcinek.
      Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.
    DOI:  https://doi.org/10.1101/cshperspect.a041199
  19. Cell. 2023 Sep 27. pii: S0092-8674(23)00975-3. [Epub ahead of print]
    Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
    Connor A Tsuchida, Nadav Brandes, Raymund Bueno, Marena Trinidad, Thomas Mazumder, Bingfei Yu, Byungjin Hwang, Christopher Chang, Jamin Liu, Yang Sun, Caitlin R Hopkins, Kevin R Parker, Yanyan Qi, Laura Hofman, Ansuman T Satpathy, Edward A Stadtmauer, Jamie H D Cate, Justin Eyquem, Joseph A Fraietta, Carl H June, Howard Y Chang, Chun Jimmie Ye, Jennifer A Doudna.
      CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the targeted chromosome, including in preclinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells (NCT03399448), reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.
    Keywords:  CAR T cells; CRISPR screen; CRISPR-Cas9; DNA repair; T cells; aneuploidy; chromosome loss; clinical trial; genome editing; immunoengineering
    DOI:  https://doi.org/10.1016/j.cell.2023.08.041
  20. Cell Rep Med. 2023 Sep 26. pii: S2666-3791(23)00381-6. [Epub ahead of print] 101214
    High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.
    Yan Cheng, Fumou Sun, Daisy V Alapat, Visanu Wanchai, David Mery, Wancheng Guo, Huojun Cao, Yuqi Zhu, Cody Ashby, Michael Anton Bauer, Intawat Nookaew, Eric R Siegel, Jun Ying, Jin-Ran Chen, Dongzheng Gai, Bailu Peng, Hongwei Xu, Clyde Bailey, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Marta Chesi, P Leif Bergsagel, Frits van Rhee, Siegfried Janz, Guido Tricot, John D Shaughnessy, Fenghuang Zhan.
      Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8+ T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development.
    Keywords:  NEK2; PD-L1; T cell immunity; bone marrow microenvironment; combination therapy; immune checkpoint blockade; interferon gamma gene signature; multiple myeloma; myeloid-derived suppressive cells; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101214
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