bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒07‒04
eleven papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Curr Opin Genet Dev. 2021 Jun 26. pii: S0959-437X(21)00074-5. [Epub ahead of print]70 83-88
      T cells undergo activation, maturation, and differentiation in which they can substantially transform and restructure. This includes metabolic adaptations which have been well recognized to be specific for T cell subsets. T cell subset-specific metabolism is thought to reflect different bioenergetic requirements as well as adaptations to environmental conditions in which the T cells operate. The metabolic changes that occur in T cells are orchestrated by signaling cascades that lead to rapid post-translational changes and through transcription factors which facilitate more long-term adaptations. In addition, metabolites produced within T cells or taken up from the environment can influence gene expression by altering chromatin accessibility or the effectiveness of transcription factors through post-translational modifications, and thus act as transcription regulators in their own right.
  2. Int J Mol Sci. 2021 Jun 24. pii: 6779. [Epub ahead of print]22(13):
      The cells of the immune system, particularly the T lymphocytes, have two main features that distinguish them from the cells of other tissues. They proliferate after activation and have the ability to move in tissues and organs. These characteristics compel them to develop metabolic plasticity in order to fulfil their immune function. This review focuses on the different known mechanisms that allow T cells to adapt their metabolism to the real-life circumstances they operate in, whether it is to exit quiescence, to differentiate into effector cells, or to participate in immune memory formation. Some of the metabolic adaptations to environmental variations that T cells are likely to undergo in their immune monitoring function are also discussed.
    Keywords:  T lymphocytes; Treg; activation; memory; metabolism
  3. Int J Mol Sci. 2021 Jun 29. pii: 7016. [Epub ahead of print]22(13):
      Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.
    Keywords:  T cells; aging; biomarker; cancer; exhaustion; immune checkpoint inhibitors; senescence
  4. Nat Commun. 2021 Jul 02. 12(1): 4098
      Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.
  5. Adv Healthc Mater. 2021 Jul 01. e2100833
      T cell exhaustion, in which dysfunctional T cells are limited in cytokine release and constrained in immune response, leads to immune escape of cancer cells and decreased efficiency of cancer immunotherapy. Direct regulation or blocking of programmed death 1 (PD-1) represents a promising strategy to overcome T cell exhaustion for reinvigorating anticancer immunity. Here, the construction of a 1,3-propanesultone (1,3-PS)-grafted zwitterionic dendrimer-entrapped gold nanoparticle platform chelated with Gd(III) (Gd-Au DENP-PS) for immune checkpoint modulation is reported. The developed Gd-Au DENP-PS possesses good stability, antifouling property, biocompatibility, and dual-mode computed tomography (CT)/magnetic resonance (MR) imaging functions, and allows for efficient packaging and serum-enhanced delivery of PD-1 siRNA to mediate PD-1 gene silencing in T cells in vitro, and also in vivo in a melanoma-bearing mouse model and in healthy aging mice. The dendrimer nanocomplexes or T cell-laden nanocomplexes enable suppression of tumor growth through the generation of significant effector CD8+ and CD4+ T cells, and the tumor immunotherapeutic potency can be further improved by combination with an indoleamine 2,3-dioxygenase inhibitor. This study identifies a new possibility with a functional dendrimer-based nanohybrid platform for dual-mode CT/MR imaging-guided cancer immunotherapy via the regulation of T cell exhaustion.
    Keywords:  T cells; dendrimers; gene silencing; immune checkpoint blockades; tumor immunotherapy
  6. Cells. 2021 Jun 22. pii: 1568. [Epub ahead of print]10(7):
      Cancer incidence increases drastically with age. Of the many possible reasons for this, there is the accumulation of senescent cells in tissues and the loss of function and proliferation potential of immune cells, often referred to as immuno-senescence. Immune checkpoint inhibitors (ICI), by invigorating immune cells, have the potential to be a game-changers in the treatment of cancer. Yet, the variability in the efficacy of ICI across patients and cancer types suggests that several factors influence the success of such inhibitors. There is currently a lack of clinical studies measuring the impact of aging and senescence on ICI-based therapies. Here, we review how cellular senescence and aging, either by directly altering the immune system fitness or indirectly through the modification of the tumor environment, may influence the cancer-immune response.
    Keywords:  aging; cancer; immune checkpoint inhibitors; senescence; tumor
  7. Int J Mol Sci. 2021 Jun 27. pii: 6913. [Epub ahead of print]22(13):
      Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states.
    Keywords:  metabolic regulation; mitochondria; mitochondrial disorders
  8. Antibodies (Basel). 2021 Jun 28. pii: 25. [Epub ahead of print]10(3):
      T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.
    Keywords:  CAR T-cells; LDHA; TME; VISTA; acidic; acidosis; lactate; lactic acid
  9. Nat Commun. 2021 Jul 01. 12(1): 4077
      Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
  10. Nat Cancer. 2021 Mar;2(3): 300-311
      While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin, and blood preferentially expressed a IFNG / TNF-high signature, which had a strong prognostic value for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and blood up to nine years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly-distributed TRM and TEM compartments.
  11. Cancers (Basel). 2021 Jun 19. pii: 3067. [Epub ahead of print]13(12):
      Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.
    Keywords:  de novo purine synthesis; glioblastoma; glioma; metabolic reprogramming; metabolic treatment; one-carbon metabolism