The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty.

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (TFH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of TFH cells have been identified in humans and mice and modifications in TFH cell phenotype and function progressively occur with age. Dysfunctional TFH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (TFR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to TFH cells in regulating immunity. Indeed, changes in TFH/TFR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both TFH cells and TFR cells that occur in aging and recent findings suggesting that TFH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.

Frailty syndrome is associated with changes in peripheral inflammatory markers in prostate cancer patients undergoing androgen deprivation therapy.

OBJECTIVE: To evaluate the role of peripheral inflammation (leukocyte differential count, the proinflammatory cytokines IL-beta, TNF-α, IL-6, IL-8, and the inflammatory markers fibrinogen and C-reactive protein [CRP]) in frailty syndrome in patients with prostate cancer (CaP) undergoing antiandrogen therapy (ADT). METHODS: A total of 46 men between 51 and 92 years of age with CaP and receiving ADT were classified as frail, prefrail or robust according to the Fried scale. A geriatric assessment was performed, based on the Minimental State Examination for cognitive function, the Barthel index for basic activities of daily living, the Yesavage scale for geriatric depression, and the Athens insomnia scale. In addition, blood samples were collected to assess peripheral inflammation biomarkers including proinflammatory cytokines, fibrinogen, CRP and leukocyte differential count, as well as other biochemical and hematological parameters. RESULTS: A significant negative correlation between the severity of frailty syndrome and lymphocyte count was observed (P < 0.01). The concentration of IL-6 (P < 0.05), CRP (P < 0.05), and fibrinogen (P < 0.01) were significantly associated with frailty syndrome, but not of TNF-α, IL-beta, or IL-8. The severity of frailty syndrome was not dependent upon the clinical disease stage at diagnosis, the time elapsed since CaP diagnosis, the presence of metastases, or prostatectomy. CONCLUSIONS: Further research into the role of leukocyte subtypes and peripheral inflammation and the associated adverse outcomes in patients with CaP under ADT is warranted in order to tailor interventions aimed at reducing symptoms of frailty syndrome, such as loss of muscle strength and low physical activity.

Toxicity of Cancer Therapies in Older Patients.

PURPOSE OF THE REVIEW: In clinical practice, older patients are often undertreated due to underrepresentation in clinical trials and fear of toxicity. Our objective was therefore to review toxicities that are specific to older cancer patients, to review risk factors in order to help physicians guide their decisions, and to review interventions that can be implemented in routine clinical practice to prevent toxicity induced by cancer therapies. RECENT FINDINGS: On the whole, reviews report similar number and frequency as well as similar grade 3 or 4 adverse events between subjects older and younger than 65 years. Yet patients included in clinical trials are often not representative of real-life patients and are often fit older cancer patients. Moreover, tolerance to the additive impact of multiple adverse effects is different between older and younger patients. And specific symptoms such as stomatitis may cause a series of consequences such as dehydration, denutrition, renal insufficiency, and adverse events of renally excreted drugs. Older patients are at high risk of toxicity due to many factors but mainly due to the prevalence of frailty in this population that has been estimated to be around 40% increasing the risk of chemotherapy intolerance. As a consequence, interventions must be implemented according to altered domains of comprehensive geriatric assessment in order to improve anticancer tolerance. These interventions are reviewed here.

Low levels of intra-tumoural T cells in breast cancer identify clinically frail patients with shorter disease-specific survival.

OBJECTIVES: The global health status of older patients with cancer influences their clinical course, but little is known regarding the influence of the immune system on the global health of older patients with cancer. The goal of this study was to assess the relationships between patient fitness/frailty status and survival, and the local tumour immune environment of older patients with breast cancer. MATERIALS AND METHODS: In a cohort of 58 older patients with breast cancer (over 70 years of age), fluorescence microscopy was used to investigate whether levels of intra-tumoural T cells (CD3+) and granulocytic cells (CD15+) could predict clinical outcome, and/or whether they correlated with patient physical and mental performance as evaluated by comprehensive geriatric assessment. RESULTS: We observed that patients with higher levels of intra-tumoural T cells were fitter according to a number of clinical health measures including G8 (p = 0.006), Karnofsky Index (p = 0.0372), and Leuven Oncology Frailty Score (LOFS) (p = 0.0187). In contrast, high relative levels of granulocytic cells were found in patients with poorer clinical health (LOFS, p = 0.0474). Furthermore, high levels of T cells but not granulocytic cells were associated with longer breast cancer-specific survival (p = 0.0444). CONCLUSIONS: This is the first study to show that low relative levels of intra-tumoural T cells are associated with inferior patient fitness. In contrast to T cells, we observed that intra-tumoural granulocytic cells displayed an inverse relationship with patient performance. Further research is needed to determine whether boosting the level of intra-tumoural T cells in older non-fit patients can result in improved outcome.

Effects of Olive Oil on TNF-α and IL-6 in Humans: Implication in Obesity and Frailty.

BACKGROUND AND OBJECTIVE: Tumor necrosis factor-alpha (TNF)-α and interleukin (IL)-6 are important mediators of chronic low-grade systemic inflammation. The latter plays a central role in several obesity-related pathologies, such as diabetes, metabolic syndrome and cardiovascular diseases. Besides, these cytokines have been also implicated in geriatric and cancer-induced anorexia, cachexia, sarcopenia and frailty. Potential interventions for both obesity and frailty include dietary advice and nutraceuticals. In this context, the consumption of olive oil (OO) has been associated with the health effects of the Mediterranean diet (Med-diet). This review is aimed to discuss the OO-mediated modulation of TNF- α and IL-6 in human studies and the potential implication in obesity and frailty. RESULTS: The reviewed studies suggest that the improvement of postprandial TNF-α and IL-6 observed with OO consumption is affected by body mass index (BMI). The effects on TNF-α and IL-6 after medium and long-term consumptions involved many factors and the cross-talk between adipose tissue, liver, skeletal muscle and brain. Major anti-inflammatory effects were observed when OO was consumed with Med-diet, which is associated with healthy behaviors. In this context, the role of microbioma- polyphenols, diet-gene and exercise-gene interactions in the effects of OO on immune-mediated inflammatory responses involved in obesity and frailty deserves further investigation. CONCLUSION: Further studies are needed to clarify the effect of OO net of possible synergistic effects with other dietary and lifestyle factors of Mediterranean area.