bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒12‒13
thirteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Cancer Lett. 2020 Dec 05. pii: S0304-3835(20)30654-6. [Epub ahead of print]
      Therapeutic efficacy of chimeric antigen receptor (CAR) T cells is associated with their expansion, persistence and effector function. Although CAR T cell therapy has shown remarkable therapeutic effects in hematological malignancies, its therapeutic efficacy has been limited in some types of cancers - in particular, solid tumors - partially due to the cells' inability to persist and the acquisition of T cell dysfunction within a harsh immunosuppressive tumor microenvironment. Therefore, it would be expected that generation of CAR T cells with intrinsic properties for functional longevity, such as the cells with early-memory phenotypes, could beneficially enhance antitumor immunity. Furthermore, because the metabolic pathways of CAR T cells help determine cellular differentiation and lifespan, therapies targeting such pathways like glycolysis and oxidative phosphorylation, can alter CAR T cell fate and durability within tumors. Here we discuss how reprogramming of CAR T cell metabolism and metabolic switch to memory CAR T cells influences their antitumor activity. We also offer potential strategies for targeting these metabolic circuits in the setting of adoptive CAR T cell therapy, aiming to better unleash the potential of adoptive CAR T cell therapy in the clinic.
  2. Science. 2020 Dec 11. 370(6522): 1328-1334
      Adoptive T cell therapy (ACT) using ex vivo-expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39-CD69-) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39+CD69+) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39+ state. However, ACT responders retained a pool of CD39- stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.
  3. Semin Cancer Biol. 2020 Dec 07. pii: S1044-579X(20)30258-3. [Epub ahead of print]
      Immune checkpoint proteins including programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are involved in proliferation, angiogenesis, metastasis, chemoresistance via immune escape and immune tolerance by disturbing cytotoxic T cell activation. Though many clinical trials have been completed in several cancers by using immune checkpoint inhibitors alone or in combination with other agents to date, recently multi-target therapy is considered more attractive than monotherapy, since immune checkpoint proteins work with other components such as surrounding blood vessels, dendritic cells, fibroblasts, macrophages, platelets and extracellular matrix within tumor microenvironment. Thus, in the current review, we look back on research history of immune checkpoint proteins and discuss their associations with platelets or tumor cell induced platelet aggregation (TCIPA) and FOXP3+ regulatory T cells (Tregs) related molecules involved in immune evasion and tumor progression, clinical implications of completed trial results and signaling networks by phytochemicals for combination therapy with immune checkpoint inhibitors and suggest future research perspectives.
    Keywords:  Immune checkpoint proteins; Tregs; clinical implications; phytochemicals; platelets; signaling networks
  4. Adv Sci (Weinh). 2020 Dec;7(23): 2002611
      Aging is a physiological decline in both structural homeostasis and functional integrity, progressively affecting organismal health. A major hallmark of aging is the accumulation of senescent cells, which have entered a state of irreversible cell cycle arrest after experiencing inherent or environmental stresses. Although cellular senescence is essential in several physiological events, it plays a detrimental role in a large array of age-related pathologies. Recent biomedical advances in specifically targeting senescent cells to improve healthy aging, or alternatively, postpone natural aging and age-related diseases, a strategy termed senotherapy, have attracted substantial interest in both scientific and medical communities. Challenges for aging research are highlighted and potential avenues that can be leveraged for therapeutic interventions to control aging and age-related disorders in the current era of precision medicine.
    Keywords:  aging; clinical trials; healthspan; senescent cells; senolytics; senotherapy
  5. Biochem J. 2020 Dec 11. pii: BCJ20200661. [Epub ahead of print]
      The integration of multiple signalling pathways that co-ordinate T cell metabolism and transcriptional reprogramming is required to drive T cell differentiation and proliferation. One key T cell signalling module is mediated by extracellular signal-regulated kinases (ERKs) which are activated in response to antigen receptor engagement. The activity of ERKs is often used to report antigen receptor occupancy but the full details of how ERKs control T cell activation is not understood. Accordingly, we have used mass spectrometry to explore how ERK signalling pathways control antigen receptor driven proteome restructuring in CD8+ T cells to gain insights about the biological processes controlled by ERKs in primary lymphocytes. Quantitative analysis of >8000 proteins identified 900 ERK regulated proteins in activated CD8+ T cells. The data identify both positive and negative regulatory roles for ERKs during T cell activation and reveal that ERK signalling primarily controls the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. It was striking that a large proportion of the proteome restructuring that is driven by triggering of the T cell antigen receptor is not dependent on ERK activation. However, the selective targets of the ERK signalling module include the critical effector molecules and the cytokines that allow T cell communication with other immune cells to mediate adaptive immune responses.
    Keywords:  T-cells; extracellular signal-regulated kinases; proteomics
  6. Proc Natl Acad Sci U S A. 2020 Dec 07. pii: 202013188. [Epub ahead of print]
      It is known that a subpopulation of T cells expresses two T cell receptor (TCR) clonotypes, though the extent and functional significance of this is not established. To definitively evaluate dual TCRα cells, we generated mice with green fluorescent protein and red fluorescent protein reporters linked to TCRα, revealing that ∼16% of T cells express dual TCRs, notably higher than prior estimates. Importantly, dual TCR expression has functional consequences, as dual TCR cells predominated response to lymphocytic choriomeningitis virus infection, comprising up to 60% of virus-specific CD4+ and CD8+ T cells during acute responses. Dual receptor expression selectively influenced immune memory, as postinfection memory CD4+ populations contained significantly increased frequencies of dual TCR cells. These data reveal a previously unappreciated contribution of dual TCR cells to the immune repertoire and highlight their potential effects on immune responses.
    Keywords:  LCMV; T cell; T cell receptor; TCR
  7. Cancer Biol Med. 2020 Nov 15. 17(4): 923-936
      Exhausted T cells are a group of dysfunctional T cells, which are present in chronic infections or tumors. The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity, reduced cytokine production, and upregulation of multiple inhibitory molecular receptors (e.g., PD-1, TIM-3, and LAG-3). The intracellular metabolic changes, altered expression of transcription factors, and a unique epigenetic landscape constitute the exhaustion program. Recently, researchers have made progress in understanding exhausted T cells, with the definition and identification of exhausted T cells changing from phenotype-based to being classified at the transcriptional and epigenetic levels. Recent studies have revealed that exhausted T cells can be separated into two subgroups, namely TCF1+PD-1+ progenitor-like precursor exhausted cells and TCF1-PD-1+ terminally differentiated exhausted T cells. Moreover, the progenitor-like precursor cell population may be a subset of T cells that can respond to immunotherapy. Studies have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic levels. TOX also maintains T cell survival and may affect decisions regarding treatment strategies. In this review, we discuss the latest developments in T cell exhaustion in regards to definitions, subpopulations, development mechanisms, differences in diverse diseases, and treatment prospects for exhausted T cells. Furthermore, we hypothesize that the epigenetic state regulated by TOX might be the key point, which can determine the reversibility of exhaustion and the efficacy of immunotherapy.
    Keywords:  T cell exhaustion; TOX; epigenetic landscape; immunotherapy; tumor immunity
  8. Immun Ageing. 2020 Nov 04. 17(1): 32
      BACKGROUND: Immune checkpoints are crucial molecules in maintaining a proper immune balance. Even though age and sex are known to have effects on the immune system, the interplay between age, sex and immune checkpoint expression by T cells is not known. The aim of this study was to determine whether age and sex affect immune checkpoint expression by T cells and if age and sex affect the kinetics of immune checkpoint expression following ex vivo stimulation. In this study, whole blood samples of 20 healthy young adults (YA, 9 males and 11 females) and 20 healthy older adults (OA, 9 males and 11 females) were stained for lymphocyte lineage markers and immune checkpoints and frequencies of CD28+, PD-1+, VISTA+ and CD40L+ T cells were determined. Immune checkpoint expression kinetics were studied following ex vivo anti-CD3/anti-CD28 stimulation of T cells from young and older healthy adults.RESULTS: We report an age-associated increase of CD40L + CD4+ and CD40L + CD8+ T-cell frequencies, whereas CD40+ B-cell frequencies were decreased in older adults, suggesting modulation of the CD40L-CD40 interaction with age. Immune checkpoint expression kinetics revealed differences in magnitude between CD4+ and CD8+ T cells independent of age and sex. Further analysis of CD4+ T-cell subsets revealed an age-associated decrease of especially PD-1 + CD4+ memory T cells which tracked with the female sex.
    CONCLUSION: Collectively, our results demonstrate that both age and sex modulate expression of immune checkpoints by human T cells. These findings may have implications for optimising vaccination and immune checkpoint immunotherapy and move the field towards precision medicine in the management of older patient groups.
    Keywords:  Age; CD28; CD40L; Immune checkpoints; PD-1; Sex; T cells; VISTA
  9. Cell. 2020 Dec 04. pii: S0092-8674(20)31536-1. [Epub ahead of print]
      Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.
    Keywords:  CD8; cytotoxic; lymphatic; recirculation; thoracic duct
  10. Nat Biotechnol. 2020 Dec 08.