Impact and potential value of immunosenescence on solid gastrointestinal tumors.

Solid gastrointestinal tumors often respond poorly to immunotherapy for the complex tumor microenvironment (TME), which is exacerbated by immune system alterations. Immunosenescence is the process of increased diversification of immune genes due to aging and other factors, leading to a decrease in the recognition function of the immune system. This process involves immune organs, immune cells, and the senescence-associated secretory phenotype (SASP). The most fundamental change is DNA damage, resulting in TME remodeling. The main manifestations are worsening inflammation, increased immunosuppressive SASP production, decreased immune cell antitumor activity, and the accumulation of tumor-associated fibroblasts and myeloid-derived suppressor cells, making antitumor therapy less effective. Senotherapy strategies to remove senescent cells and block key senescence processes can have synergistic effects with other treatments. This review focuses on immunoenescence and its impact on the solid TME. We characterize the immunosenescent TME and discuss future directions for antitumor therapies targeting senescence.

Innate Immune Responses of Vaccinees Determine Early Neutralizing Antibody Production After ChAdOx1nCoV-19 Vaccination.

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.

hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis.

Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-ß-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-ß-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.

Immune Checkpoint Inhibitors in the Aged.

PURPOSE OF REVIEW: Large phase III trials have established the benefit of checkpoint blockade across multiple tumor types, but patient representation is limited in some subgroups including the aged population. There are several changes in the immune system that occur with age (termed immunosenescence) that could potentially limit efficacy in aged populations. RECENT FINDINGS: Despite the concerns stated above, available evidence from prospective trials, retrospective cohorts, and registry data suggest that elderly patients achieve similar benefit with immune checkpoint blockade in comparison to the general population and do not have increased toxicity. However, as patients age, they are at higher risk of developing a decline in multiple physiologic systems (including the immune system) and reduced ability to recover from illness. Clinical evidence shows that patients who have a poor performance status have inferior outcomes and limited clinical benefit from checkpoint blockade. Clinicians should take an individualized approach that accounts for each patient's health status rather than considering age alone when determining who should be offered checkpoint blockade therapy.

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System.

Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.

Reduced naïve T cell numbers correlate with increased low-grade systemic inflammation during ageing and can be modulated by physical activity / Un número reducido de células T vírgenes se correlaciona con un aumento de la inflamación sistémica de bajo grado durante el envejecimiento y puede ser modulado por la actividad física

SUMMARY: Age-associated decline of immune system, termed immunosenescence, is characterized by low-grade systemic inflammation, known as inflammaging, together with T-cell functional dysregulation. Although affecting all individuals, different environmental as well genetic factors impinge on the individual´s susceptibility or resilience to immunosenescence. Physical activity has been shown to improve autonomy and functionality in older adults. However, if physical activity affects immunosenescence or inflammaging remains unknown. The purpose of this study was to analyze immunosenescence and inflammaging in elderly individuals by measuring peripheral naïve T cells and interleukin (IL) -6 from peripheral blood and evaluate the impact of physical activity on T cell dysregulation and inflammaging. Thirty (30) elderly volunteers (10 males and 20 females), and 7 young controls (2 males ad 7 females), were recruited for this study. A methodology questionnaire was used to evaluate different parameters such as physical activity, and peripheral naïve CD4+ and CD8+ T cells and serum IL-6 were measured by FACS and ELISA respectively. Our results shown that naïve T cells decline, and IL-6 levels increase as older people age. Interestingly, we observed strong negative correlation between naïve T cells numbers and IL-6 levels in older adults, suggesting a direct link between reduced naïve T cell pool and increased inflammaging. Continuous physical activity during youth did not affect immunosenescence and inflammaging in elderly, but physical activity during elderly increase naïve T cell numbers and reduce inflammaging in older subjects. Our results showed reduced number of naïve T cells and increased levels of IL-6 as elder people get older. Moreover, the strong negative correlation between these parameters suggest that naïve T cells can have a direct suppressive activity over innate immune components. Furthermore, physical activity during elderly can reduce immunosenescence and inflammaging in older subjects.

RESUMEN: El deterioro del sistema inmunológico asociado con la edad, denominado inmunosenescencia, se caracteriza por una inflamación sistémica de bajo grado, conocida como inflamaging, junto con una desregulación funcional de las células T. Aunque afectan a todos los individuos, diferentes factores ambientales y genéticos inciden en la susceptibilidad o resiliencia del individuo a la inmunosenescencia. Estudios anteriores han demostrado que la actividad física mejora la autonomía y la funcionalidad en los adultos mayores, aunque como la actividad física impacta a la inmunosenescencia e inflammaging es aún desconocido. El propósito de este estudio fue analizar la inmunosenescencia e inflammaging en personas de edad avanzada, midiendo las células T vírgenes y la interleucina (IL)-6 de sangre periférica, junto con evaluar el impacto de la actividad física sobre la inflamación basal y la inmunosenescencia. Treinta voluntarios ancianos (10 hombres y 20 mujeres) y 7 controles jóvenes (2 hombres y 5 mujeres) fueron incluidos en este estudio. Para medir actividad física, autonomía y dependencia se utilizó un cuestionario de metodología, junto con evaluar el número de células T CD4+ y CD8+ periféricas vírgenes e IL-6 sérica mediante FACS y ELISA, respectivamente. Nuestros resultados muestran que las células T vírgenes disminuyen y los niveles de IL-6 aumentan a medida que las personas mayores envejecen. Curiosamente, observamos una fuerte correlación negativa entre el número de células T vírgenes y los niveles de IL-6 en adultos mayores, lo que sugiere un vínculo directo entre la reducción de la reserva de células T vírgenes y el aumento de la inflamación. La actividad física durante la juventud no afectó la inmunosenescencia ni la inflamación en los ancianos, pero la actividad física durante la vejez aumenta el número de células T vírgenes y reduce la inflamación en los adultos mayores. Estos resultados sugieren que inmunosenescencia e inflammaging parecen estar directamente conectados, además de concluir que el desarrollo de actividad física durante la vejez reduce la inmunosenescencia y la inflamación basal en adultos mayores.

Methods for Characterization of Senescent Circulating and Tumor-Infiltrating T-Cells: An Overview from Multicolor Flow Cytometry to Single-Cell RNA Sequencing.

Immunosenescence is the general term used to describe the aging-associated decline of immunological function that explains the higher susceptibility to infectious diseases and cancer, increased autoimmunity, or the reduced effectiveness of vaccinations. Senescence of CD8+ T-cells has been described in all these conditions.The most important classical markers of T senescent cells are the cell cycle inhibitors p16ink4a, p21, and p53, together with positivity for SA-ßgal expression and the acquirement of a peculiar IFNγ -based secretory phenotype commonly defined SASP (Senescence Associated Secretory Phenotype). Other surface markers are the CD28 and CD27 loss together with gain of expression of CD45RA, CD57, TIGIT, and/or KLRG1. However, this characterization could not be sufficient to distinguish from truly senescent cells and exhausted T-cells. Furthermore, more complexity is added by the wide heterogeneity of T-cells subset in aged individuals or in the tumor microenvironment. A combined analysis by multicolor flow cytometry for surface and intracellular markers integrated with gene-expression arrays and single-cell RNA sequencing is required to develop effective interventions for therapeutic modulation of specific T-cell subsets. The RNASeq offers the great possibility to reveal at single-cell resolution the exact molecular hallmarks of senescent CD8+ T-cells without the limitations of bulk analysis. Furthermore, the comprehensive integration of multidimensional approaches (genomics, epigenomics, proteomics, metabolomics) will increase our global understanding of how immunosenescence of T-cells is interlinked to human aging.

Progressive multifocal leukoencephalopathy in an elderly immunocompetent-appearing patient: Relevance with L-selectin (CD62L) expression and immunosenescence.

Progressive multifocal leukoencephalopathy (PML) is attributed to reactivation of the John Cunningham virus (JCV), in the central nervous system as a result of immunosuppression. Low L-selectin (CD62L) expression on cryopreserved T-cells has been advocated as a biomarker for natalizumab related PML in patients with Relapsing-Remitting Multiple Sclerosis. A rare case of PML in an elderly patient without known factors of immunosuppression or immunomodulation is hereby presented. T-cell L-selectin expression levels and serum anti-JCV antibody index were evaluated in order to explore mechanistic insight to the pathways that presumably contribute towards PML development in this rare clinical setting.

Interrogation of the cellular immunome of cancer patients with regard to the COVID-19 pandemic.

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis.

Introduction: Residual immune dysfunctions, resembling those that occur during normal aging, may persist even in well-treated people with HIV (PWH), and accelerated aging has been proposed. We aimed to determine if HIV infection is an independent risk factor for T-cell immune dysfunctions including increased immune activation, senescence and apoptosis. Moreover, in PWH we aimed to identify the associations between age and immune activation, senescence and apoptosis. Materials and Methods: We included 780 PWH with suppressed viral replication (<50 copies/mL) and absence of hepatitis B and hepatitis C co-infection and 65 uninfected controls from the Copenhagen Co-morbidity in HIV Infection (COCOMO) Study. Flow cytometry was used to determine T-cell activation (CD38+HLA-DR+), senescence (CD28-CD57+), and apoptosis (CD28-CD95+). T-cell subsets are reported as proportions of CD4+ and CD8+ T-cells. We defined an elevated proportion of a given T-cell subset as above the 75th percentile. Regression models were used to determine the association between HIV status and T-cell subset and in PWH to determine the association between age or HIV-specific risk factors and T-cell subsets. Furthermore, an interaction between HIV status and age on T-cell subsets was investigated with an interaction term in models including both PWH and controls. Models were adjusted for age, sex, BMI, and smoking status. Results: In adjusted models a positive HIV status was associated with elevated proportions of CD8+ activated (p = 0.009), CD4+ senescent (p = 0.004), CD4+ apoptotic (p = 0.002), and CD8+ apoptotic (p = 0.003) T-cells. In PWH a 10-year increase in age was associated with higher proportions of CD4+ and CD8+ senescent (p = 0.001 and p < 0.001) and CD4+ and CD8+ apoptotic T-cells (p < 0.001 and p < 0.001). However, no interaction between HIV status and age was found. Furthermore, in PWH a CD4+/CD8+ ratio < 1 was associated with elevated proportions of T-cell activation, senescence, and apoptosis. Discussion: We found evidence of residual T-cell immune dysfunction in well-treated PWH without HBV or HCV co-infection, and age was associated with T-cell senescence and apoptosis. Our data supports that HIV infection has similar effects as aging on T-cell subsets. However, since no interaction between HIV status and age was found on these parameters, we found no evidence to support accelerated immunological aging in PWH.

Childhood survivors of high-risk neuroblastoma show signs of immune recovery and not immunosenescence.

Neuroblastoma survivors show signs of immunosenescence early after therapy in CD8+ T cell compartment and elevated plasma TNF-α but in later follow-up immune recovery comes into play. Whether the recovery phenotype is long lasting or transient remains to be elucidated, however, late adverse effects often occur in childhood cancer survivors.

The paradigm of immunosenescence in atherosclerosis-cardiovascular disease (ASCVD).

The new immunosenescence paradigm (2015) was an attempt to explain a mechanism by which macrophages could be immunosuppressed and dysfunctional, yet paradoxically release proinflammatory factors in an unregulated manner. This mechanism was linked to the loss of dehydroepiandrosterone (DHEA) with aging and thus explained how immunosenescence could be causally related to the risk of stress and/or age-associated chronic diseases. At the center of this paradigm was lipid body negative (LB-) foamy macrophage (CD14+CD16+) which produced human endogenous retrovirus K102 (HERV-K102) particles. HERV-K102 may be a protector foamy virus of humans, and its induction may generate trained innate immunity, a special type of autoimmunity, in response to intracellular pathogens, their constituents, toxins, and/or tumors. Overwhelming evidence now suggests that the proinflammatory foamy macrophages driving ASCVD are LB-. Moreover, the monocyte/macrophage phenotype implicated in atherosclerosis-cardiovascular disease (ASCVD) appears to be the CD14+CD16+ intermediate phenotype. These and other observations directly challenge the cholesterol hypothesis. For the prevention and treatment of ASCVD, it is important to address the putative cause of ASCVD -- immunosenescence, rather than the signs or symptoms such as inflammation or elevated cholesterol. Therefore, strategies to reverse or prevent immunosenescence, which improve or maintain an optimal cortisol/DHEA ratio such as isoflavonoids, would be expected to alleviate not only ASCVD but the risk of many other age-associated chronic diseases. Here, the new immunosenescence paradigm will be appraised for its suitability to explain ASCVD risks.

CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses.

Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4+ and CD8+ T cells of elderly individuals. Aged CD70+ T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70+ T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70+ T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

Is background methotrexate advantageous in extending TNF inhibitor drug survival in elderly patients with rheumatoid arthritis? An analysis of the British Society for Rheumatology Biologics Register.

OBJECTIVE: To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults. METHODS: Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: <75 and ≥75. Cox-proportional hazards models compared the risk of TNFi discontinuation from (i) any-cause, (ii) inefficacy and (iii) adverse events, between patients prescribed TNFi-monotherapy compared with TNFi MTX combination. RESULTS: The analysis included 15 700 patients. Ninety-five percent were <75 years old. Comorbidity burden and disease activity were higher in the ≥75 cohort. Fifty-two percent of patients discontinued TNFi therapy during the follow-up period. Persistence with therapy was higher in the <75 cohort. Patients receiving TNFi monotherapy were more likely to discontinue compared with patients receiving concomitant MTX [hazard rate 1.12 (1.06-1.18) P <0.001]. This finding only held true in patients <75 [hazard rate (HR) 1.11 (1.05-1.17) vs ≥75 [HR 1.13 (0.90-1.41)]. Examining TNFi discontinuation by cause revealed patients ≥75 receiving TNFi monotherapy were less likely to discontinue TNFi due to inefficacy [HR 0.66 (0.43-0.99) P=0.04] and more likely to discontinue therapy from adverse events [HR 1.41(1.02-1.96) P =0.04]. These results were supported by the multivariate adjustment in complete case and imputed analyses. CONCLUSION: TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.

cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model.

Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2'3 cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.

Interstitial Lung Disease in Elderly Rheumatoid Arthritis Patients.

The increase in life expectancy together with better care of rheumatoid arthritis (RA) has led to higher proportions of elderly individuals with RA. This has challenged the treatment of the disease in older aged patients, usually characterized by comorbid conditions and polypharmacy. Overall, the lung involvement in RA is present in up to 80% of patients, depending on the assessment tools used, and interstitial abnormalities are among the most common; when present, interstitial lung disease (ILD) worsens the prognosis of RA, and is the second most common cause of mortality. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis of the lung. Therefore, ILD tends to occur more frequently in older patients with RA. The age at onset of RA distinguishes patients as having young-onset RA (YORA, < 60 years) or late-onset RA (LORA, > 60 years); the latter are characterized by more severe features of the disease and higher rates of lung involvement. The most frequent RA-related ILD radiological pattern is usual interstitial pneumonia (UIP); this includes peripheral and basal predominant reticulation and honeycombing with or without associated traction bronchiectasis. Patients with the UIP pattern are usually older and have more rapid decline in lung function and a worse prognosis. Treatment with corticosteroids in elderly patients carries the risk of adverse effects, such as osteoporosis, infections, diabetes, peptic ulcers, and cataract. The use of disease-modifying antirheumatic drugs (DMARDs) is generally well-tolerated by the elderly. The current narrative review aims at elucidating the association between ILD and RA in older individuals.

Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention.

Aging is accompanied by remodeling of the immune system. With time, this leads to a decline in immune efficacy, resulting in increased vulnerability to infectious diseases, diminished responses to vaccination, and a susceptibility to age-related inflammatory diseases. An age-associated immune alteration, extensively reported in previous studies, is the reduction in the number of peripheral blood naïve cells, with a relative increase in the frequency of memory cells. These two alterations, together with inflamm-aging, are considered the hallmarks of immunosenescence. Because aging is a plastic process, it is influenced by both nutritional and pharmacological interventions. Therefore, the role of nutrition and of immunomodulation in immunosenescence is discussed, due to the multifactorial influence on these hallmarks. The close connection between nutrition, intake of bioactive nutrients and supplements, immune function, and inflammation demonstrate the key role of dietary strategies as regulators of immune response and inflammatory status, hence as possible modulators of the rate of immunosenescence. In addition, potential options for therapeutic intervention are clarified. In particular, the use of interleukin-7 as growth factor for naïve T cells, the function of checkpoint inhibitors in improving T cell responses during aging and, the potential of drugs that inhibit mitogen-activated protein kinases and their interaction with nutrient signaling pathways are discussed. Finally, it is suggested that the inclusion of appropriate combinations of toll-like receptor agonists may enhance the efficacy of vaccination in older adults.

Cellular Senescence and the Immune System in Cancer.

In response to a variety of cancer-inducing stresses, cells may engage a stable cell cycle arrest mechanism, termed cellular senescence, to suppress the proliferation of preneoplastic cells. Despite this cell intrinsic tumor suppression, senescent cells have also been implicated as active contributors to tumorigenesis by extrinsically promoting many hallmarks of cancer, including evasion of the immune system. Here, we discuss these dual, and seemingly contradictory, roles of senescence during tumorigenesis. Furthermore, we highlight findings of how senescent cells can influence the immune system and discuss the possibility that immune cells themselves may be acquiring senescence-associated alterations. Lastly, we discuss how senescent cell avoidance or clearance may impact pathology.

A Mathematical Model of the Effects of Aging on Naive T Cell Populations and Diversity.

The human adaptive immune response is known to weaken in advanced age, resulting in increased severity of pathogen-born illness, poor vaccine efficacy, and a higher prevalence of cancer in the elderly. Age-related erosion of the T cell compartment has been implicated as a likely cause, but the underlying mechanisms driving this immunosenescence have not been quantitatively modeled and systematically analyzed. T cell receptor diversity, or the extent of pathogen-derived antigen responsiveness of the T cell pool, is known to diminish with age, but inherent experimental difficulties preclude accurate analysis on the full organismal level. In this paper, we formulate a mechanistic mathematical model of T cell population dynamics on the immunoclonal subpopulation level, which provides quantitative estimates of diversity. We define different estimates for diversity that depend on the individual number of cells in a specific immunoclone. We show that diversity decreases with age primarily due to diminished thymic output of new T cells and the resulting overall loss of small immunoclones.

Does patient age influence anti-cancer immunity?

Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient's own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to (i) their low amounts of naïve T cells (potentially leading to holes in the repertoire for neoantigens), (ii) "exhaustion" of potentially tumor-specific memory T cells, and (iii) higher amounts of suppressive cells. Encouragingly, but only anecdotally, accumulated clinical experience suggests that advanced age does not result in poorer responses or greater toxicity in elderly patients treated with anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. Here, I briefly contrast immune features of the elderly with the young, commonly referred to as "immunosenescence," and the influence of patient age on the outcome of checkpoint blockade. As newer agents are licensed, and new combinations tested, broader and more detailed studies focusing on the age question will be crucial and should be taken into consideration when designing clinical trials.