bims-imseme 2022-10-02 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–10–02
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Time isn't kind to female T-cells.
Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
Upregulation of PD-L1 in Senescence and Aging.
Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance.
Targeting T Cell Metabolism as a Novel Approach for Treatment of MS: With a Focus on PFKFB3 Inhibitors.
PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.
Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging - from theory to practice.
PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Nat Aging. 2022 Mar;2(3): 189-191

Time isn't kind to female T-cells.

Cassandra J McGill, Bérénice A Benayoun.

While investigating sex-differences in T-cell aging, Mkhikian et al., identified a role for excessive IL-7 signaling and N-glycan branching in age-related mouse and human female T-cell dysfunction. These findings point to the increasingly-recognized importance of the impact of biological sex on immune aging and delineate new targetable pathways in age-related immune dysfunction.

DOI: https://doi.org/10.1038/s43587-022-00185-0
Science. 2022 Sep 30. 377(6614): 1519-1529

Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.

Giulia Notarangelo, Jessica B Spinelli, Elizabeth M Perez, Gregory J Baker, Kiran Kurmi, Ilaria Elia, Sylwia A Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J Golby, Shakchhi Joshi, Heide F Baron, Jefte M Drijvers, Peter Georgiev, Alison E Ringel, Elma Zaganjor, Samuel K McBrayer, Peter K Sorger, Arlene H Sharpe, Kai W Wucherpfennig, Sandro Santagata, Nathalie Y R Agar, Mario L Suvà, Marcia C Haigis.

Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.

DOI: https://doi.org/10.1126/science.abj5104
Mol Cell Biol. 2022 Sep 26. e0017122

Upregulation of PD-L1 in Senescence and Aging.

Angelique Onorati, Aaron P Havas, Brian Lin, Jayaraj Rajagopal, Payel Sen, Peter D Adams, Zhixun Dou.

  Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.

Keywords:  PD-L1; SASP; aging; senescence

DOI:  https://doi.org/10.1128/mcb.00171-22
Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2204296119

Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance.

Manpreet K Semwal, Allison K Hester, Yangming Xiao, Chioma Udeaja, Sergio Cepeda, John S Verschelde, Nicholas Jones, Sarah A Wedemeyer, Simon Emtage, Kymberly Wimberly, Ann V Griffith.

  Thymic stromal cells (TSCs) are critical regulators of T cell tolerance, but their basic biology has remained under-characterized because they are relatively rare and difficult to isolate. Recent work has revealed that constitutive autophagy in TSCs is required for self-antigen presentation and central T cell tolerance induction; however, the mechanisms regulating constitutive autophagy in TSCs are not well understood. Hydrogen peroxide has been shown to increase autophagy flux in other tissues, and we previously identified conspicuously low expression of the hydrogen peroxide-quenching enzyme catalase in TSCs. We investigated whether the redox status of TSCs established by low catalase expression regulates their basal autophagy levels and their capacity to impose central T cell tolerance. Transgenic overexpression of catalase diminished autophagy in TSCs and impaired thymocyte clonal deletion, concomitant with increased frequencies of spontaneous lymphocytic infiltrates in lung and liver and of serum antinuclear antigen reactivity. Effects on clonal deletion and autoimmune indicators were diminished in catalase transgenic mice when autophagy was rescued by expression of the Becn1F121A/F121A knock-in allele. These results suggest a metabolic mechanism by which the redox status of TSCs may regulate central T cell tolerance.

Keywords:  thymus; tolerance

DOI:  https://doi.org/10.1073/pnas.2204296119
Endocr Metab Immune Disord Drug Targets. 2022 Sep 21.

Targeting T Cell Metabolism as a Novel Approach for Treatment of MS: With a Focus on PFKFB3 Inhibitors.

Mahsa Eshkevar Vakili, Fateme Nezhad Shah Mohammadi, Mohammad Reza Ataollahi, Keivan Shams, Kari K Eklund, Gholamreza Daryabor, Kurosh Kalantar.

  Multiple sclerosis (MS) is one of the organ-specific autoimmune diseases in which immune cells invade the neurons in the central nervous system (CNS) due to loss of tolerance to self-antigens. Consequently, inflammation and demyelination take place in the central nervous system. The pathogenesis of MS is not completely understood. However, it seems that T cells, especially Th17 cells, have an important role in the disease development. In recent years, studies on manipulation of metabolic pathways with therapeutic targets have received increasing attention and have had promising results in some diseases such as cancers. Glycolysis is a central metabolic pathway and plays an important role in the differentiation of T CD4+ cell toward its subsets, especially the Th17 cells. This suggests that manipulation of glycolysis, by for example using appropriate safe inhibitors of this pathway, can represent a means to affect the differentiation of T CD4+, thus reducing inflammation and disease activity in MS patients. Hence, in this study we aimed to discuss evidence showing that using inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3), as the main regulator of glycolysis, may exert beneficial effects on MS patients.

Keywords:  Multiple sclerosis; PFKB3; TH17 cells; autoimmunity; glycolysis; inflammation

DOI:  https://doi.org/10.2174/1871530322666220921160930
Nature. 2022 Sep 28.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.

Laura Codarri Deak, Valeria Nicolini, Masao Hashimoto, Maria Karagianni, Petra C Schwalie, Laura Lauener, Eleni Maria Varypataki, Marine Richard, Esther Bommer, Johannes Sam, Stefanie Joller, Mario Perro, Floriana Cremasco, Leo Kunz, Emilio Yanguez, Tamara Hüsser, Ramona Schlenker, Marisa Mariani, Vinko Tosevski, Sylvia Herter, Marina Bacac, Inja Waldhauer, Sara Colombetti, Xavier Gueripel, Stephan Wullschleger, Melanie Tichet, Douglas Hanahan, Haydn T Kissick, Stephane Leclair, Anne Freimoser-Grundschober, Stefan Seeber, Volker Teichgräber, Rafi Ahmed, Christian Klein, Pablo Umaña.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

DOI: https://doi.org/10.1038/s41586-022-05192-0
Front Nutr. 2022 ;9 958563

Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging - from theory to practice.

Carla Luís, Ana T Maduro, Paula Pereira, José João Mendes, Raquel Soares, Renata Ramalho.

  Aging is a natural physiological process, but one that poses major challenges in an increasingly aging society prone to greater health risks such as diabetes, cardiovascular disease, cancer, frailty, increased susceptibility to infection, and reduced response to vaccine regimens. The loss of capacity for cell regeneration and the surrounding tissue microenvironment itself is conditioned by genetic, metabolic, and even environmental factors, such as nutrition. The senescence of the immune system (immunosenescence) represents a challenge, especially when associated with the presence of age-related chronic inflammation (inflammaging) and affecting the metabolic programming of immune cells (immunometabolism). These aspects are linked to poorer health outcomes and therefore present an opportunity for host-directed interventions aimed at both eliminating senescent cells and curbing the underlying inflammation. Senotherapeutics are a class of drugs and natural products that delay, prevent, or reverse the senescence process - senolytics; or inhibit senescence-associated secretory phenotype - senomorphics. Natural senotherapeutics from food sources - nutritional senotherapeutics - may constitute an interesting way to achieve better age-associated outcomes through personalized nutrition. In this sense, the authors present herein a framework of nutritional senotherapeutics as an intervention targeting immunosenescence and immunometabolism, identifying research gaps in this area, and gathering information on concluded and ongoing clinical trials on this subject. Also, we present future directions and ideation for future clinical possibilities in this field.

Keywords:  aging; immunometabolism; immunosenescence; inflammaging; nutritional senolytics; nutritional senomorphics; precision nutrition

DOI:  https://doi.org/10.3389/fnut.2022.958563
Nature. 2022 Sep 28.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Masao Hashimoto, Koichi Araki, Maria A Cardenas, Peng Li, Rohit R Jadhav, Haydn T Kissick, William H Hudson, Donald J McGuire, Rebecca C Obeng, Andreas Wieland, Judong Lee, Daniel T McManus, James L Ross, Se Jin Im, Junghwa Lee, Jian-Xin Lin, Bin Hu, Erin E West, Christopher D Scharer, Gordon J Freeman, Arlene H Sharpe, Suresh S Ramalingam, Alex Pellerin, Volker Teichgräber, William J Greenleaf, Christian Klein, Jorg J Goronzy, Pablo Umaña, Warren J Leonard, Kendall A Smith, Rafi Ahmed.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

DOI: https://doi.org/10.1038/s41586-022-05257-0