The role of T cells in age-related diseases

Carrasco, Elisa; Heras, Manuel M. Gómez de las; Gabandé‐Rodríguez, Enrique; Desdín-Micó, Gabriela; Aranda, Juan; Mittelbrunn, Marı́a

doi:10.1038/s41577-021-00557-4

Cited by 117 publications

(92 citation statements)

References 195 publications

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“…Microenvironmental immune gene sets are known to be differentially expressed between children and adults with AML (Vadakekolathu et al, 2020b; Willier et al, 2021), which may in part be due to differences in pediatric versus adult AML biology (Bolouri et al, 2018; Conneely and Stevens, 2021; de Rooij et al, 2015; Tarlock and Meshinchi, 2015). Furthermore, immunosenescence, a process of remodeling of immune functions upon chronic antigen exposure, is associated with physiologic aging (Carrasco et al, 2021; Mittelbrunn and Kroemer, 2021). We thus examined the relevance and applicability of the IES score to childhood AML and first analyzed diagnostic BM samples from 145 pediatric patients with de novo AML in the Children’s Oncology Group (COG)-TARGET AML cohort for whom RNA-sequencing data are publicly available (Bolouri et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Rutella

Vadakekolathu

Mazziotta

et al. 2022

Preprint

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The function of senescent-like T cells, transcriptomic features of immune effector senescence (IES) and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,864 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). We show that senescent-like bone marrow CD8+ T cells are impaired in killing autologous AML blasts, and that their proportion negatively correlates with overall survival. We define new IES signatures using two gene expression platforms and report that IES scores correlate with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or LSC17 stemness score. IES expression signatures also identify an ICB-unresponsive tumor microenvironment and predict significantly worse OS in AML as well as in solid tumors. The newly described IES scores provide improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.

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Section: Resultsmentioning

confidence: 99%

Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Rutella

Vadakekolathu

Mazziotta

et al. 2022

Preprint

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“…As T cells are not produced de novo in the thymus in adults, the production of naïve T cells relies on the homeostatic proliferation of existing naïve T cell pools. Impaired homeostatic proliferation, differentiation to memory cells upon chronic antigen exposure, and failed quiescence together lead to decreased naïve T cell pools in the elderly ( Goronzy and Weyand, 2019 ; Carrasco et al, 2021 ). In addition, thymic involution contributes to the generation and accumulation of autoreactive T cells in peripheral organs, including the brain, and a higher risk of autoimmune diseases ( Coder et al, 2015 ).…”

Section: Central Nervous System-immune Interactions During Aging and Neurodegenerationmentioning

confidence: 99%

Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases

Rickenbach

Gericke

2022

Front. Neurosci.

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The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.

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“…Additionally, the spectrum of T cells shifts to a predominantly memory T-cell pool, which leads to decreases in the T-cell receptor repertoire. 115 In turn, these cells contribute to age-associated dysfunction of the immune system. In the breast, functional shifts in immune cell proportions occur, with increased bone marrow-derived macrophages, which propagate pro-tumour inflammation.…”

Section: Translational Science: Insights To Guide New Therapiesmentioning

confidence: 99%

Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women

Carleton

Nasrazadani

Gade

et al. 2022

The Lancet Healthy Longevity

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Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers—specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients’ lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.

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The role of T cells in age-related diseases

Cited by 117 publications

References 195 publications

Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases

Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women

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