An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

Lanna, Alessio; Vaz, Bruno; D’Ambra, Clara; Valvo, Salvatore; Vuotto, Claudia; Chiurchiù, Valerio; Devine, Oliver; Sanchez, Massimo; Borsellino, Giovanna; Akbar, Arne N.; Bardi, Marco De; Gilroy, Derek W.; Dustin, Michael L.; Blumer, Brendan; Karin, Michael

doi:10.1038/s41556-022-00991-z

Cited by 60 publications

(53 citation statements)

References 48 publications

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“…Telomeres may lengthen due to the activity of the enzyme telomerase [105] and other mechanisms (e.g. [106,107]). Somatic telomerase activity has been detected in tissues of some species, including birds [108], but is generally thought to be repressed in large bodied and long-lived species as a mechanism of tumor suppression [109,110].…”

Section: Discussionmentioning

confidence: 99%

Longitudinal telomere dynamics within natural lifespans of a wild bird

Pepke

Kvalnes

Wright

et al. 2022

Preprint

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Telomeres, the nucleotide sequences that protect the ends of eukaryotic chromosomes, shorten with each cell division and telomere loss may be increased by factors such as oxidative stress. Telomere length (TL) decreases with age in several species, and TL or the change in TL (∆TL) have emerged as biomarkers reflecting experienced stress. In this study, we tracked changes in TL throughout the natural lifespan (from a few months to almost 9 years) of free-living house sparrows (Passer domesticus) in two different island populations. TL was measured in nestlings and subsequently up to 4 times during their lifetime. TL generally decreased with age (senescence), but we also observed instances of telomere lengthening within individuals. We found some evidence for selective disappearance of individuals with shorter telomeres through life. Early-life TL positively predicted later-life TL, but the within-individual repeatability in TL was low (9.2%). Using genetic pedigrees, we found a moderate heritability of ∆TL (h2 = 0.21), which was higher than the heritabilities of early-life TL (h2 = 0.14) and later-life TL measurements (h2 = 0.15). Cohort effects explained considerable proportions of variation in early-life TL (60%), later-life TL (53%), and ∆TL (37%), which suggests persistent impacts of the early-life environment on lifelong telomere dynamics. Individual changes in TL were independent of early-life TL. Finally, there was weak evidence for population differences in ∆TL that may be linked to ecological differences in habitat types. Combined, our results show that individual telomere biology is highly dynamic and influenced by both genetic and environmental variation in natural conditions.

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Section: Discussionmentioning

confidence: 99%

Longitudinal telomere dynamics within natural lifespans of a wild bird

Pepke

Kvalnes

Wright

et al. 2022

Preprint

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“…RNAse treatment suppressed these effects, suggesting the role of RNAs contained in EVs in the regulation of telomere function. In a more recent study, telomere vesicle transfer from antigen-presenting cells elongated telomeres in recipient T cells independently of telomerase activity [ 41 ].…”

Section: Role Of Evs In the Aging Processmentioning

confidence: 99%

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

Sanz-Ros

Mas-Bargues

Romero-García

et al. 2022

IJMS

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Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases.

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“…Telomeres are TTAGGG repeats that are located at chromosome ends, and their length determines cellular lifespan. Recent studies have shown that intercellular transfer of telomeres rescues T cell senescence and promotes long-term immune memory [ 175 ]. Based on this finding, scientists may be able to try to lengthen telomeres during T-cell activation, so that the life span of engineered CAR T-cells can be prolonged.…”

Section: Outlooksmentioning

confidence: 99%

Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

Chen

Lü

2022

Cancers

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Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.

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An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

Cited by 60 publications

References 48 publications

Longitudinal telomere dynamics within natural lifespans of a wild bird

Longitudinal telomere dynamics within natural lifespans of a wild bird

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

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