bims-imseme 2024-11-24 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–11–24
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.
Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.
Nanotube-mediated mitochondrial transfer: power to the T cells!
Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.
Dysfunctional bronchoalveolar effector memory CD8+ T cells in tuberculosis-exposed people living with antiretroviral-naïve HIV infection.
Glycolysis regulated exosomal LINC01214 inhibited CD8+ T cell function and induced anti-PD1 resistance in melanoma via modulating miR-4492/PPP1R11 axis.
[The role of immunosenescence and inflammaging in aging-associated diseases].
Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy.
A novel designed anti-PD-L1/OX40 bispecific antibody augments both peripheral and tumor-associated immune responses for boosting anti-tumor immunity.

Mol Cancer. 2024 Nov 19. 23(1): 260

Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.

Mei-Qi Yang, Shu-Ling Zhang, Li Sun, Le-Tian Huang, Jing Yu, Jie-Hui Zhang, Yuan Tian, Cheng-Bo Han, Jie-Tao Ma.

  Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.

Keywords:  Cancer immunotherapy; Epigenetics; Mitochondria; Mitochondria metabolism; Mitochondrial dynamics; T cell exhaustion

DOI:  https://doi.org/10.1186/s12943-024-02175-9
Elife. 2024 Nov 20. pii: RP96812. [Epub ahead of print]13

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.

Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles Drake, Drew Pardoll.

  The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

Keywords:  Treg; autoimmunity; cell fate; effector T cell; electric state; immunology; inflammation; metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.96812
Trends Immunol. 2024 Nov 20. pii: S1471-4906(24)00272-2. [Epub ahead of print]

Nanotube-mediated mitochondrial transfer: power to the T cells!

Cosima T Baldari.

The success of T cell-based immunotherapies is limited by exhaustion, which is associated with mitochondrial dysfunction. Baldwin and colleagues show that bone marrow stromal cells (BMSCs) use nanotubes to transfer mitochondria to T cells, which increases mitochondria mass and fitness and boosts antitumor efficacy. The results pave the way to organelle-based therapies against cancer.

DOI: https://doi.org/10.1016/j.it.2024.11.001
Aging Cell. 2024 Nov 17. e14409

Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.

Katie L Reagin, Rae-Ling Lee, Luke A Williams, Loren Cocciolone, Kristen E Funk.

  Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post-infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection.

Keywords:  CD8+ T cells; aging; cognitive dysfunction; murine hepatitis virus; neuroinflammation; resident memory T cells; respiratory infection

DOI:  https://doi.org/10.1111/acel.14409
iScience. 2024 Nov 15. 27(11): 111137

Dysfunctional bronchoalveolar effector memory CD8+ T cells in tuberculosis-exposed people living with antiretroviral-naïve HIV infection.

Maphe Mthembu, Helgard Claassen, Sharon Khuzwayo, Valentin Voillet, Anneta Naidoo, Jule S Spillner, Kennedy Nyamande, Dilshaad Fakey Khan, Priya Maharaj, Mohammed Mitha, Zoey Mhlane, Farina Karim, Erica Andersen-Nissen, Thumbi Ndung'u, Gabriele Pollara, Emily B Wong.

  HIV causes susceptibility to respiratory pathogens, including tuberculosis (TB), but the underlying immunological mechanisms remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from TB-exposed people in the presence or absence of antiretroviral-naïve HIV co-infection. Bulk transcriptional profiling demonstrated compartment-specific enrichment of immunological processes. Systems-level deconvolution of whole blood from people living with HIV identified elevated type I and type II interferon cytokine activity and T cell proliferation. Transcriptional modules derived from both peripheral blood and sorted BAL immune cells demonstrated an increased frequency of effector memory CD8 T cells in whole BAL samples. Both compartments displayed reduced induction of CD8 T-cell-derived interleukin-17A (IL-17A) in people with HIV, associated with elevated T cell regulatory molecule expression. The data suggest that dysfunctional CD8 T cell responses in uncontrolled HIV may contribute to compromised respiratory immunity to pathogens, a process that could be modulated by host-directed therapies that target CD8 T cell effector functions.

Keywords:  Immunology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.111137
Noncoding RNA Res. 2025 Feb;10 242-251

Glycolysis regulated exosomal LINC01214 inhibited CD8+ T cell function and induced anti-PD1 resistance in melanoma via modulating miR-4492/PPP1R11 axis.

Zhi Ding, Baojin Wu, Junyi Yang, Daohe Wang, Jing Qiao, Fanli Guo.

   Background: Long non-coding RNAs (lncRNAs) can be incorporated into exosomes to mediate the intercellular communication, regulating the occurrence, development, and immunosuppression of cancers. T cell dysfunction has been a hallmark of many cancers, including melanoma, which enables cancer cells escape from host immune surveillance. However, the molecular mechanism of exosome-transmitted lncRNAs in CD8+ T cell dysfunction in melanoma remains largely unclear.
Method: The expression of circulating LINC01214 (cirLINC01214) was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Exosomes were isolation from the culture medium and plasma of melanoma patients via ultracentrifugation and characterized by transmission electronic microscopy. The regulation of exosomal LINC01214 on CD8+ T cell function was determined by ELISA. The molecular mechanism of exosomal LINC01214 in CD8+ T cells were assessed by the RNA immunoprecipitation and pull-down assay. A mouse model with reconstituted human immune system was used to explore the role of exosomal LINC01214 in the resistance to anti-PD1 therapy.
Results: LINC01214 was highly expressed in melanoma tissues compared with matched adjacent normal tissues. Increased levels of circulating LINC01214 (cirLINC01214) was observed in melanoma patient plasma and correlated with poor PD-1 immunotherapy response. The cirLINC01214 was predominantly released by melanoma cells in an exosome manner. Melanoma cell-derived exosomal LINC01214 inhibits the production of IFN-γ, TNF-α, Granzyme-B and Perforin by CD8+ T cells. Further mechanism study found that cirLINC01214 delivered by exosomes suppressed CD8+ T cell function by up-regulating the expression of Protein Phosphatase 1 Regulatory Inhibitor Subunit 11 (PPP1R11) through sponging miR-4492. CirLINC01214 conferred resistance to PD-1 immunotherapy in melanoma xenograft mouse model. Melanoma patients with poor prognosis after PD-1 treatment carried high levels of exosomal LINC01214. Additionally, the secretion of exosomal cirLINC01214 was enhanced by the Warburg effect, which was consistent with the reprogrammed glucose metabolism of melanoma.
Conclusions: Our results demonstrated that exosomal LINC01214 released by melanoma cells promoted immunotherapy resistance by inducing CD8+ T cell dysfunction via the miR-4492/PPP1R11 regulatory loop. Targeting cirLINC01214 might be a potential therapeutic strategy to enhance the outcome of immunotherapy in melanoma.

Keywords:  CD8+ T; Exosome; LINC01214; Melanoma; PD-1

DOI:  https://doi.org/10.1016/j.ncrna.2024.10.005
Rev Med Inst Mex Seguro Soc. 2024 Sep 02. pii: e6025. [Epub ahead of print]62(5): 1-8

[The role of immunosenescence and inflammaging in aging-associated diseases].

María Teresa García-de la Rosa, Isabel Wong-Baeza, Lourdes Andrea Arriaga-Pizano.

  With the increase in the number of people with advanced age (> 60 years) worldwide, it is necessary to understand the processes that lead to healthy aging. Cellular senescence, immunosenescence and inflammaging are part of the natural process of aging and are associated with age-related diseases. Cellular senescence is characterized by the arrest of the cell cycle in the G1 phase. Senescent cells can be identified by different markers (surface or intracellular), by changes in their functions, and by their gene expression profile. Immunosenescence causes dysregulation of the immune response, with persistent (chronic) increases in inflammatory mediators and decreases in the effectiveness of immune effector responses, which promotes the development and severity of chronic-degenerative diseases and fragility. When immunosenescence is related with advanced age, it is known as inflammaging. New strategies to revert immunosenescence are currently being investigated, with senotherapy with senolytic drugs that eliminate senescent cells, and with senomorphic drugs that inhibit the secretion of senescence-promoting mediators. Senolytic drugs may be useful during the aging process, to delay, prevent and/or improve age-related diseases.

Keywords:  Aging; Immunosenescence; Inflammation

DOI:  https://doi.org/10.5281/zenodo.12668114
bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]

Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.

Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.

The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.

DOI: https://doi.org/10.1101/2024.10.30.621159
Mol Ther Oncol. 2024 Dec 19. 32(4): 200897

A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy.

Mathias Wenes, Anouk Lepez, Vladimir Arinkin, Kinsey Maundrell, Orsolya Barabas, Federico Simonetta, Valérie Dutoit, Pedro Romero, Jean-Claude Martinou, Denis Migliorini.

  Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell in vivo expansion and long-term persistence. We previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma. Here, we use a novel MPC inhibitor, MITO-66, which robustly induces a stem cell-like memory phenotype in CD19-CAR T cells generated from healthy donors and patients with relapsed/refractory B cell malignancies. MITO-66-conditioned CAR T cells were superior in controlling human pre-B cell acute lymphoblastic leukemia in mice. Following adoptive cell transfer, MITO-66-conditioned CAR T cells maintained a memory phenotype and protected cured mice against tumor rechallenge. Furthermore, in an in vivo B cell leukemia stress model, CD19-CAR T cells generated in the presence of MITO-66 largely outperformed clinical-stage AKT and PI-3Kδ inhibitors. Thus, we provide compelling preclinical evidence that MPC inhibition with MITO-66 during CAR T cell manufacturing dramatically enhances their antitumor efficacy, thereby paving the way to clinical translation.

Keywords:  CAR T cell manufacture; CAR T cell therapy; MT: Regular Issue; immunometabolism; memory T cell differentiation; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.1016/j.omton.2024.200897
Mol Cancer Ther. 2024 Nov 22.

A novel designed anti-PD-L1/OX40 bispecific antibody augments both peripheral and tumor-associated immune responses for boosting anti-tumor immunity.

Baocun Li, Shiyong Gong, Nianying Zhang, Beilei Shi, Zhou Lv, Yu Zhang, Naren Gaowa, Liqin Dong, Danqing Wu, Jianfu Wu, Fan Liu, Rui Zhang, Ramin Behzadigohar, Vinod Ganju, Chengbin Wu, Xuan Wu.

Bispecific antibodies (BsAbs) combining simultaneous PD-L1 blockade and conditional co-stimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared to ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T cell activation. EMB-09 demonstrated improved anti-tumor activity compared to the anti-PD-L1 monoclonal antibody. Significantly, EMB-09 activated effector memory T cells in peripheral immune system, promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0330