bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒09‒19
seventeen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. J Clin Invest. 2021 Sep 15. pii: 152382. [Epub ahead of print]131(18):
      T cell exhaustion is an evocative concept that results in attenuated function in the face of chronic antigen exposure and is critical to avoid immunopathology. However, tumors often exploit this dampened T cell function to escape the antitumor immune response. In this issue of the JCI, You et al. investigated a different aspect of T cell exhaustion in the setting of tumor immunity by characterizing the capacity of T cells for tireless migration. The dynamic nature of normal T cells was first made famous by intravital microscopy studies in explanted tissues. You et al. used a similar imaging strategy with reanimated human tumors, in which exhausted T cells displayed an enhanced capacity for intratumoral motility. These results suggest that exhausted T cells may be able to teach T cell engineers lessons about navigating within the tumor microenvironment.
  2. Front Immunol. 2021 ;12 725618
      T cell stemness and exhaustion coexist as two key contrasting phenomena during chronic antigen stimulation, such as infection, transplant, cancer, and autoimmunity. T cell exhaustion refers to the progressive loss of effector function caused by chronic antigen exposure. Exhausted T (TEX) cells highly express multiple inhibitory receptors and exhibit severe defects in cell proliferation and cytokine production. The term T cell stemness describes the stem cell-like behaviors of T cells, including self-renewal, multipotency, and functional persistence. It is well accepted that naïve and some memory T cell subsets have stem cell-like properties. When investigating the exhaustive differentiation of T cells in chronic infection and cancer, recent studies highlighted the stemness of "precursors of exhausted" T (TPEX) cells prior to their terminal differentiation to TEX cells. Clinically successful checkpoint blockades for cancer treatment appear to invigorate antitumor TPEX cells but not TEX cells. Here we discuss the transcriptional and epigenetic regulations of T cell stemness and exhaustion, with a focus on how systems immunology was and will be utilized to define the molecular basis underlying the transition of TPEX to TEX cells. We suggest a "stepwise model" of T cell stemness and exhaustion, in which loss of stemness and exhaustion progression are gradual multi-step processes. We provide perspectives on the research needed to define T cell stemness and exhaustion in the transplantation setting, in which allogenic T cells are also chronically exposed to alloantigens. A better understanding of T cell stemness and exhaustion will shed light on developing novel strategies for immunotherapies.
    Keywords:  T cell; T cell exhaustion; T cell stemness; epigenetic regulation; transcription factor; transplantation
  3. Mol Oncol. 2021 Sep 17.
      Programmed cell death-1 (PD-1) signaling downregulates the T cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared to PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anti-cancer immune response in future immunotherapy approaches.
    Keywords:  Drp1; PD-1; T cell; mitochondria; tumor-infiltrating lymphocytes
  4. Cell Rep. 2021 Sep 14. pii: S2211-1247(21)01146-3. [Epub ahead of print]36(11): 109699
      Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3+ Treg cells may be a relevant therapeutic target cell type for the treatment of cancer.
    Keywords:  T cell immunoglobulin and mucin 3 (Tim-3); cellular metabolism; cellular signaling; immunosuppression; regulatory T cells (Treg); tumor immunology
  5. Cell Rep. 2021 Sep 14. pii: S2211-1247(21)01143-8. [Epub ahead of print]36(11): 109696
      CD4 T cells are essential for immunity to tuberculosis because they produce cytokines, including interferon-γ. Whether CD4 T cells act as "helper" cells to promote optimal CD8 T cell responses during Mycobacterium tuberculosis is unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growth in vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 T cell responses against M. tuberculosis infection in vitro and in vivo. We infer vaccines that elicit both CD4 and CD8 T cells are more likely to be successful than vaccines that elicit only CD4 or CD8 T cells.
    Keywords:  CD4 T cell help; CD4 T cells; CD8 T cells; CTL; T cell exhaustion; immunity; infection; interferon gamma; lung; mycobacterium tuberculosis
  6. iScience. 2021 Sep 24. 24(9): 103020
      Despite the obvious inhibitory outcome of PD-1 signaling, an additional series of functions are activated. We have observed that T cells stimulated through the T cell receptor (TCR) and PD-1 primarily do not proliferate; however, there is a population of cells that proliferates more than through TCR stimulation alone. In this study, we performed flow cytometry and RNA sequencing on individual populations of T cells and discovered that unlike naive T cells, which were inhibited following PD-1 ligation, T cells that proliferated more following PD-1 ligation were associated with effector and central memory phenotypes. We showed that these populations had different gene expression profiles following PD-1 ligation with PD-L1 compared to PD-L2. The presence of transcriptionally and functionally distinct T cell populations responsive to PD-1 ligation provides new insights into the biology of PD-1 and suggest the use of T cell subset-specific approaches to improve the clinical outcome of PD-1 blockade.
    Keywords:  Cancer; Immunology; Transcriptomics
  7. Nature. 2021 Sep 15.
      Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.
  8. Immunity. 2021 Sep 13. pii: S1074-7613(21)00352-6. [Epub ahead of print]
      How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4+ T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 immunotherapy leads to an increased TCR signal strength. We defined a strong TCR signal metric of five genes upregulated by anti-PD1 in T cells (TCR.strong), which was superior to a canonical T cell activation gene signature in stratifying melanoma patient outcomes to anti-PD1 therapy. Our study therefore reveals how analysis of TCR signal strength-and its manipulation-can provide powerful metrics for monitoring outcomes to immunotherapy.
    Keywords:  ICOS; IRF8; Nr4a3; OX40; PD1; TCR signaling; TCR.strong; immunotherapy; melanoma; nivolumab
  9. Cell Chem Biol. 2021 Sep 11. pii: S2451-9456(21)00363-9. [Epub ahead of print]
      Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of programmed cell death protein 1 (PD-1) blockade, leading to better cancer treatment. Although epigenetic drugs showed potential in combination therapy, the lack of sequence specificity is a major concern. Here, we identify and develop a DNA-based epigenetic activator with tri-arginine vector called EnPGC-1 that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1α/β), a regulator of mitochondrial biogenesis. EnPGC-1 enhances mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhances oxidative phosphorylation, a feature of long-lived memory T cells. Genome-wide gene analysis suggests that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade to enhance antitumor immunity and improved host survival.
    Keywords:  PD-1; T-cell activation; cancer immunotherapy; combination therapy; epigenetic activator; mitochondrial biogenesis; oxidative phosphorylation; pyrrole-imidazole polyamide; therapeutic gene modulation
  10. Mech Ageing Dev. 2021 Sep 09. pii: S0047-6374(21)00141-X. [Epub ahead of print] 111569
      Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme in redox reactions. NAD+ is also important in cellular signalling as it is consumed by PARPs, SARM1, sirtuins and CD38. Cellular NAD+ levels regulate several essential processes including DNA repair, immune cell function, senescence, and chromatin remodelling. Maintenance of these cellular processes is important for healthy ageing and lifespan. Interestingly, the levels of NAD+ decline during ageing in several organisms, including humans. Declining NAD+ levels have been linked to several age-related diseases including various metabolic diseases and cognitive decline. Decreasing tissue NAD+ concentrations have been ascribed to an imbalance between biosynthesis and consumption of the dinucleotide, resulting from, for instance, reduced levels of the rate limiting enzyme NAMPT along with an increased activation state of the NAD+-consuming enzymes PARPs and CD38. The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+.
    Keywords:  NAD biosynthesis; NAD metabolism; PARP; Sirtuins; ageing
  11. Immunology. 2021 Sep 16.
      Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-β-induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2 , which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2 -EP2/EP4 signalling interrupts TGF-β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2 -EP2/EP4 pathway to control T cell-mediated inflammation.
    Keywords:  EP receptors; Foxp3; Inflammation; Prostaglandin E2; Regulatory T cell; TGF-β
  12. Immunity. 2021 Sep 08. pii: S1074-7613(21)00360-5. [Epub ahead of print]
      In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity.
    Keywords:  CD8 T cells; Flt3L; T cell dysfunction; TCF-1+; anti-CD40; migratory cDC1; single-cell RNA-seq; tumor immunology; tumor-draining lymph node
  13. J Nutr Biochem. 2021 Sep 10. pii: S0955-2863(21)00281-3. [Epub ahead of print] 108861
      Adequate nutrition is vital for immune homeostasis. However, the incidence of obesity is increasing worldwide due to the adoption of the Western diet and a sedentary lifestyle. Obesity is associated with chronic inflammation which alters the function of adipose tissue, liver, pancreas, and the nervous system. Inflammation is related to cellular senescence, distinguished by irreversible cell cycle arrest. Senescent cells secrete the senescence-associated secretory phenotype (SASP) which contains pro-inflammatory factors. Targeting processes in senescence might have a salutary approach to obesity. The present review highlights the impact of an unhealthy diet on tissues affected by obesity, and the mechanisms that promote the consequent inflammation and senescence.
    Keywords:  aging; diet; inflammation; microbiota obesity; senescence
  14. Mech Ageing Dev. 2021 Sep 10. pii: S0047-6374(21)00139-1. [Epub ahead of print] 111567
      NAD+ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD+, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD+ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD+ replenishment through NAD+ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer's disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies. Major NAD+ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD+ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; NAD(+); ageing; healthspan
  15. Immunity. 2021 Sep 14. pii: S1074-7613(21)00351-4. [Epub ahead of print]54(9): 2117-2132.e7
      The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.
    Keywords:  CD69; CD8 T cells; CXCR6; Cancer; TCR; TRP-2; Trm; parabiosis; scRNA-seq; vitiligo
  16. Trends Cell Biol. 2021 Sep 09. pii: S0962-8924(21)00163-X. [Epub ahead of print]
      Solute carrier transporters (SLCs) mediate nutrient and metabolite cellular homeostasis. Immune cells depend on SLCs to induce rapid and robust metabolic reprogramming, thereby controlling diverse immunological responses. Recent studies hint toward an important role of SLCs in immunity. Here, we review the emerging roles of SLCs in immunotherapy via modifying the metabolism and effector functions of immune cells. We focus on the roles of three major nutrient (glucose, amino acid, and lipid)-related transporters in immunity of representative cells [T cells, dendritic cells (DCs), natural killer (NK) cells, and macrophages) in innate and adaptive immunity. Other SLCs, such as ion transporters are also briefly discussed. Finally, we propose some potential strategies for targeting SLCs to augment tumour immunotherapy.
    Keywords:  immunocyte; metabolic reprogramming; nutrient and metabolite; solute carrier transporter; tumour immunotherapy
  17. Nat Protoc. 2021 Sep 17.
      Cancer cells undergo diverse metabolic adaptations to meet the energetic demands imposed by dysregulated growth and proliferation. Assessing metabolism in intact tumors allows the investigator to observe the combined metabolic effects of numerous cancer cell-intrinsic and -extrinsic factors that cannot be fully captured in culture models. We have developed methods to use stable isotope-labeled nutrients (e.g., [13C]glucose) to probe metabolic activity within intact tumors in vivo, in mice and humans. In these methods, the labeled nutrient is introduced to the circulation through an intravenous catheter prior to surgical resection of the tumor and adjacent nonmalignant tissue. Metabolism within these tissues during the infusion transfers the isotope label into metabolic intermediates from pathways supplied by the infused nutrient. Extracting metabolites from surgical specimens and analyzing their isotope labeling patterns provides information about metabolism in the tissue. We provide detailed information about this technique, from introduction of the labeled tracer through data analysis and interpretation, including streamlined approaches to quantify isotope labeling in informative metabolites extracted from tissue samples. We focus on infusions with [13C]glucose and the application of mass spectrometry to assess isotope labeling in intermediates from central metabolic pathways, including glycolysis, the tricarboxylic acid cycle and nonessential amino acid synthesis. We outline practical considerations to apply these methods to human subjects undergoing surgical resections of solid tumors. We also discuss the method's versatility and consider the relative advantages and limitations of alternative approaches to introduce the tracer, harvest the tissue and analyze the data.