Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence.

Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8+ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)+ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2+ tumor cells are induced to produce transforming growth factor ß to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8+ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2+ tumor cells driving CD8+ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8+ T cell senescence for chemoradiotherapy recurrence.

VEGFR affects miR-3200-3p-mediated regulatory T cell senescence in tumour-derived exosomes in non-small cell lung cancer.

Numerous studies have demonstrated that regulatory T (Treg) cells play an important role in the tumour microenvironment (TME). The aim of this study was to investigate whether VEGFR2 affects the expression of miR-3200-3p in exosomes secreted by tumour cells, thereby influencing Treg senescence in the TME. The results showed that VEGFR2 expression level was the highest in Calu-1 cells, and after transfection with si-VEGFR2, the exosomes secreted from Calu-1 cells were extracted and characterised with no significant difference from the exosomes of the untransfected group, but the expression of miR-3200-3p in the exosomes of the transfected si-VEGFR2 group was elevated. The Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM) results suggested that exosomes highly expressing miR-3200-3p could inhibit Treg cell viability and promote apoptosis levels when treated with Treg cells. Detection of the senescence-associated proteins p16 INK4A and MMP3 by western blot (WB) revealed that exosomes highly expressing miR-3200-3p were able to elevate their protein expression levels. Tumour xenograft experiments demonstrated that exosomes with high miR-3200-3p expression promoted Treg cell senescence and inhibited subcutaneous tumour growth in nude mice. Dual-luciferase reporter assays and RNA pull-down assays showed that miR-3200-3p could be linked with DDB1. Overexpression of DDB1 reverses changes in DCAF1/GSTP1/ROS protein expression caused by exosomes with high miR-3200-3p expression. In conclusion, inhibition of VEGFR2 expression in tumour cells promotes the expression of miR-3200-3p in exosomes secreted by tumour cells. miR-3200-3p enters the TME through exosomes and acts on DDB1 in Treg cells to promote senescence of Treg cells to inhibit tumour progression.

T cell senescence: a new perspective on immunotherapy in lung cancer.

T cell senescence is an indication of T cell dysfunction. The ability of senescent T cells to respond to cognate antigens is reduced and they are in the late stage of differentiation and proliferation; therefore, they cannot recognize and eliminate tumor cells in a timely and effective manner, leading to the formation of the suppressive tumor microenvironment. Establishing methods to reverse T cell senescence is particularly important for immunotherapy. Aging exacerbates profound changes in the immune system, leading to increased susceptibility to chronic, infectious, and autoimmune diseases. Patients with malignant lung tumors have impaired immune function with a high risk of recurrence, metastasis, and mortality. Immunotherapy based on PD-1, PD-L1, CTLA-4, and other immune checkpoints is promising for treating lung malignancies. However, T cell senescence can lead to low efficacy or unsuccessful treatment results in some immunotherapies. Efficiently blocking and reversing T cell senescence is a key goal of the enhancement of tumor immunotherapy. This study discusses the characteristics, mechanism, and expression of T cell senescence in malignant lung tumors and the treatment strategies.

The Impact of T-cell Aging on Alloimmunity and Inflammaging.

Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined "inflammaging," accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general "weaker" alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.

Gut Microbiota Richness and Diversity Track With T Cell Aging in Healthy Adults.

BACKGROUND: This study examined how gut microbiota diversity and richness relate to T cell aging among 96 healthy adults of all ages. It also explored whether these links differed throughout the lifespan. METHODS: Peripheral blood was obtained from 96 study participants (N = 96, aged 21-72) to assess mRNA markers of T cell aging (p16ink4a, p14ARF, B3gat1, Klrg1) and DNA methylation. T cell aging mRNA markers were combined into an aging index, and the Horvath epigenetic clock algorithm was used to calculate epigenetic age based on DNA methylation status of over 500 loci. Participants also collected a stool sample from which the V4 region of the 16S rRNA gene was sequenced to derive the Shannon and Simpson diversity indices, and the total count of observed operational taxonomic units (richness). Models controlled for BMI, comorbidities, sex, dietary quality, smoking status, physical activity, and sleep quality. RESULTS: Lower microbiota richness was associated with higher T cell age based on mRNA markers, but when probing the region of significance, this relationship was only significant among adults 45 years and older (p = .03). Lower Shannon diversity (p = .05) and richness (p = .07) marginally correlated with higher epigenetic age (ie, greater T cell DNA methylation). CONCLUSIONS: Gut microbiota complexity may correspond with the rate of T cell aging, especially in mid-to-late life. These results suggest an interplay between the gut microbiome and immunological aging that warrants further experimental work.