Are immunosenescent T cells really senescent?

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases.

Case discussion: The effect of extreme temperatures on an older adult.

Climate change can cause high temperatures that can affect the older adult in significant ways. Older adults may not be aware of the dangers of high temperature days and may continue with old habits such as staying in the sun to garden without sunscreen or a hat as they may have done in years past. High temperatures can cause impairment of the tone and structure of blood vessels by interfering with nitric oxide synthesis and cytokine production and can cause systemic inflammation, all of which significantly contribute to dehydration in older adults, who are known to have a decreased sense of thirst, resulting in increased blood viscosity and the risk of heat induced shock and thrombotic strokes. This case discussion highlights the effects of high temperatures due to climate change on an older adult, and what nurse practitioners need to be aware of when assessing older adults who may be suffering from heat exhaustion or heat stroke, and how to manage appropriately.

The Relationship Between Financial Stress and Job Performance in China: The Role of Work Engagement and Emotional Exhaustion.

Purpose: Economic pressure has become an important source of stress for employees. However, the conclusions regarding the relationship between financial stress and employees' work behavior are not consistent. The present study explored the relationship between financial stress and employee job performance with a Chinese sample and further explored how and when financial stress influenced job performance. Samples and Methods: The present study investigated five distinct companies operating in diverse sectors using a convenience sampling technique. Three hundred and twenty-one employees were recruited. Financial Stress, Job Performance, Work Engagement, and Emotional Exhaustion were measured for this investigation. The mediation effect was tested using a four-step procedure. The analysis of the moderated mediation model was performed using Hayes's PROCESS macro for SPSS. Results: The results found financial stress was positively related to job performance, and work engagement mediated the positive relationship between financial stress and job performance. In addition, emotional exhaustion moderated the mediating process between financial stress, work engagement, and job performance. Specifically, the beneficial effect of financial stress on work engagement disappeared when emotional exhaustion was high. Besides, a high level of emotional exhaustion weakened the positive relationship between work engagement and job performance. Conclusion: Financial stress plays a motivating role in employees' job performance in China. Work engagement is a key factor between financial stress and job performance. Notably, the positive effect of financial stress and work engagement on job performance is contingent upon the individual's level of emotional exhaustion. These results might explain the inconsistency of the effect of financial stress in previous research. Moreover, this finding suggests that emotional factors may not only be the result of stress but can also influence its effects.

LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.

Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.

Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity.

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

terraFlow, a high-parameter analysis tool, reveals T cell exhaustion and dysfunctional cytokine production in classical Hodgkin's lymphoma.

Immune cells express an incredible variety of proteins; by measuring combinations of these, cell types influencing disease can be precisely identified. We developed terraFlow, a platform that defines cell subsets exhaustively by combinatorial protein expression. Using high-parameter checkpoint-focused and function-focused panels, we studied classical Hodgkin's lymphoma (cHL), where systemic T cells have not been investigated in detail. terraFlow revealed immune perturbations in patients, including elevated activated, exhausted, and interleukin (IL)-17+ phenotypes, along with diminished early, interferon (IFN)γ+, and tumor necrosis factor (TNF)+ T cells before treatment; many perturbations remained after treatment. terraFlow identified more disease-associated differences than other tools, often with better predictive power, and included a non-gating approach, eliminating time-consuming and subjective manual thresholds. It also reports a method to identify the smallest set of markers distinguishing study groups. Our results provide mechanistic support for past reports of immune deficiency in cHL and demonstrate the value of terraFlow in immunotherapy and biomarker studies.

Dual targeting chimeric antigen receptor cells enhance antitumour activity by overcoming T cell exhaustion in pancreatic cancer.

BACKGROUND AND PURPOSE: Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs. EXPERIMENTAL APPROACH: In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo. KEY RESULTS: Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-ß dependent manner. CONCLUSION AND IMPLICATIONS: The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.

DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer.

Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8+T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

The Importance of Training to Manage a Church as a Predictor of Emotional Exhaustion and Ministry Satisfaction.

The study found that pastors who agreed they were trained to manage a church ranked high in ministry satisfaction and low in emotional exhaustion compared to those who disagreed to receiving such training. This work has implications for seminaries, congregations, denominational leaders and clergy themselves to ensure clergy are properly prepared and continue their career journey. This study could be used to modify curricula at seminaries and produce post seminary training and educational information.

Corrigendum: Modulation of natural killer cell exhaustion in the lungs: the key components from lung microenvironment and lung tumor microenvironment.

[This corrects the article DOI: 10.3389/fimmu.2023.1286986.].

T cell exhaustion in human cancers.

T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.

Running on empty: Exploring stem cell exhaustion in geriatric musculoskeletal disease.

Ageing populations globally are associated with increased musculoskeletal disease, including osteoporosis and sarcopenia. These conditions place a significant burden of disease on the individual, society and the economy. To address this, we need to understand the underpinning biological changes, including stem cell exhaustion, which plays a key role in the ageing of the musculoskeletal system. This review of the recent evidence provides an overview of the associated biological processes. The review utilised the PubMed/Medline, Science Direct, and Google Scholar databases. Mechanisms of ageing identified involve a reaction to the chronic inflammation and oxidative stress associated with ageing, resulting in progenitor cell senescence and adipogenic differentiation, leading to decreased mass and quality of both bone and muscle tissue. Although the mechanisms underpinning stem cell exhaustion are unclear, it remains a promising avenue through which to identify new strategies for prevention, detection and management.

Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

Blockade of PD-1 and TIM-3 Ameliorates CD8+ T Cell Exhaustion in a Mouse Model of Chronic Myeloid Leukemia.

The immune system plays a pivotal role in controlling chronic myeloid leukemia (CML). CD8+ T cell exhaustion results in reduced effectiveness of T cell-mediated immunity, thereby contributing to disease progression. This study intends to figure out whether the combined blockade of inhibitory molecules TIM-3/PD-1 can affect CD8+ T cell exhaustion in CML. A CML mouse model was established via transplantation of bone marrow cells transduced with BCR-ABL-expressing retrovirus vectors. PD-1 and TIM-3 signaling were blocked using corresponding molecular antibodies. Flow cytometry analysis was conducted to detect cell surface molecules and intracellular cytokines. ELISA was employed for measuring cytokine concentrations in the culture medium. The results showed that TIM-3 and PD-1 were coexpressed on exhausted CD8+ T cells from CML mice. Combined blockade of PD-1/TIM3 synergistically delayed CML progression in mice. Moreover, ex vivo experiments showed that their co-blockade promoted the proliferation and cytokine secretion of CD8+ T cells isolated from CML mice. In conclusion, blocking TIM-3 and PD-1 improves exhausted CD8+ T cell function in CML.

New HCC Subtypes Based on CD8 Tex-Related lncRNA Signature Could Predict Prognosis, Immunological and Drug Sensitivity Characteristics of Hepatocellular Carcinoma.

Purpose: Hepatocellular carcinoma has become one of the severe diseases threatening human health. T cell exhaustion is deemed as a reason for immunotherapy resistance. However, little is known about the roles of CD8 Tex-related lncRNAs in HCC. Materials and Methods: We processed single-cell RNA sequencing to identify CD8 Tex-related genes. CD8 Tex-related lncRNAs were identified based on their correlations with mRNAs. Unsupervised clustering approach was used to identify molecular clusters of CD8 Tex-related lncRNAs. Differences in prognosis and immune infiltration between the clusters were explored. Machine learning algorithms were used to construct a prognostic signature. Samples were classified as low- and high-risk groups based on their risk scores. We identified prognosis-related lncRNAs and constructed a ceRNA network. In vitro experiments were conducted to investigate the impacts of CD8 Tex-related lncRNAs on proliferation and apoptosis of HCC cells. Results: We clarified cell types within two HCC single-cell datasets. We identified specific markers of CD8 Tex cells and analyzed their potential functions. Twenty-eight lncRNAs were identified as CD8 Tex-related. Based on CD8 Tex-related lncRNAs, samples were categorized into two distinct clusters, which exhibited significant differences in survival rates and immune infiltration. Ninety-six algorithm combinations were employed to establish a prognostic signature. RSF emerged as the one with the highest C-index. Patients in high- and low-risk groups exhibited marked differences in prognosis, enriched pathways, mutations and drug sensitivities. MCM3AP-AS1, MAPKAPK5-AS1 and PART1 were regarded as prognosis-related lncRNAs. A ceRNA network was constructed based on CD8 Tex-related lncRNAs and mRNAs. Experiments on cell lines and organoids indicated that downregulation of MCM3AP-AS1, MAPKAPK5-AS1 and PART1 suppressed cell proliferation and induced apoptosis. Conclusion: CD8 Tex-related lncRNAs played crucial roles in HCC progression. Our findings provided new insights into the regulatory mechanisms of CD8 Tex-related lncRNAs in HCC.

Anti-TIM3 chimeric antigen receptor-natural killer cells preferentially target primitive acute myeloid leukemia cells with minimal fratricide and exhaustion.

Acute myeloid leukemia (AML) is an aggressive and genetically heterogeneous disease with poor clinical outcomes. Refractory AML is common, and relapse remains a major challenge, attributable to the presence of therapy-resistant leukemic stem cells (LSCs), which possess self-renewal and repopulating capability. Targeting LSCs is currently the most promising avenue for long-term management of AML. Likewise, chimeric antigen receptor (CAR)-natural killer (NK) cells have emerged as a promising alternative to CAR-T cells due to their intrinsic potential as off-the-shelf products and safer clinical profiles. Here, we introduced a third-generation CAR harboring TIM3 scFv, CD28, 4-1BB, and CD3ζ (CAR-TIM3) into human NK-92 cells, the only FDA-approved NK cell line for clinical trials. TIM3 was chosen as a target antigen owing to its differential expression in LSCs and normal hematopoietic stem/progenitor cells (HSPCs). The established CAR-TIM3 NK-92 cells effectively targeted TIM3 and displayed potent anti-tumor activity against various primitive AML cells, subsequently causing a reduction in leukemic clonogenic growth in vitro, while having minimal effects on HSPCs. CAR-TIM3 NK-92 cells significantly reduced leukemic burden in vivo and interestingly suppressed the engraftment of AML cells into the mouse liver and bone marrow. Surprisingly, we found that CAR-TIM3 NK-92 cells expressed relatively low surface TIM3, leading to a low fratricidal effect. As TIM3 and PD-1 are immune checkpoints involved in NK cell dysfunction, we further tested and found that CAR-TIM3 NK-92 cells are beneficial for alleviating NK cell exhaustion. Our findings highlight the potential application of CAR-TIM3 NK cells for cellular immunotherapy for TIM3+ AML.

Midlife stress-related exhaustion and dementia incidence: a longitudinal study over 50 years in women.

BACKGROUNDS: Cognitive problems are common symptoms among individuals with stress-related exhaustion. It is still unknown whether these individuals are at a higher risk of developing dementia later. This study aims to examine the relationship between midlife stress-related exhaustion and dementia incidence. METHODS: A population sample of 777 women (aged 38, 46, 50 and 54 years) without dementia at baseline was followed over 50 years, from 1968 to 2019. Stress-related exhaustion was based on information from the psychiatric examination in 1968/69. Information on dementia incidence between 1968 and 2019 was obtained from neuropsychiatric examinations, key-informant interviews, and hospital registry. Dementia was diagnosed according to the DSM-III-R criteria. A subgroup of non-demented women (n = 284) was examined for cognitive functions by the Gottfries-Bråne-Steen scale 24 years after baseline. RESULTS: Stress-related exhaustion in midlife was associated with higher risk for development of dementia before age 75 (Hazard ratio and 95% confidence interval: 2.95 and 1.35-6.44). The association remained after adjustment for age, major depression, and anxiety disorder. Mean age of dementia onset was younger for women with stress-related exhaustion than women without stress (mean ± SD, 76 ± 9 vs. 82 ± 8 . p = 0.009). Women with stress-related exhaustion in midlife still showed more cognitive impairments 24 years later compared with women without stress (Odds ratio and 95% confidence interval: 2.64 and 1.15-6.06). CONCLUSIONS: We found that women with stress-related exhaustion in midlife were at a higher risk to develop dementia at relatively younger age. These women showed persistently lower cognitive functions over years even without dementia. Present study results need to be interpreted with caution due to small sample size and should be confirmed in future studies with larger sample size. Our study findings may imply the importance of long-term follow-up regarding cognitive function among individuals with stress-related exhaustion.