Immune Risk Profile Research Articles

Abstract PO5-24-10: Clinical significance and immune landscape analyses of the immune related genes based prognostic signature for HER2 positive breast cancer

Abstract Objective: To date, significant breakthrough has yet to be achieved in immunotherapy for HER2-positive breast cancer (HPBC). In this study, we aimed to construct a risk model for predicting prognosis and therapy response and evaluating the tumor immune landscape in HPBC patients. Methods: Differentially expressed immune-related genes (IRGs) were used as input to weighted correlation network analysis (WGCNA) to identify modules of highly correlated gene. An optimal prognostic TPBC-IRGs signature were constructed by least absolute shrinkage and selection operator (LASSO) cox regression. Survival analysis and ROC curves were analyzed to identify the predictive value in a training cohort and external validation cohorts. With three GEO datasets and samples from our center, the anti-HER2 therapeutic efficacy in HPBC patients was predicted through this prognostic model. Additionally, the immunotherapy outcome was forecasted using IMvigor210 dataset. We also investigated the connection between high and low-risk populations and immune checkpoints and analyzed immune infiltration levels of these populations with several algorithms. Ultimately, we develop a combined model and nomogram by integrating the risk score with clinical factors. Results: 11 key genes associated with overall survival (OS) in the blue module were selected for further analysis. A 3-gene signature (CX3CL1, RARB, TANK) based prognostic risk model was developed. The Kaplan-Meier survival curve revealed that patients with high-risk score had shorter OS compared with the low-risk group. The AUC of the training cohort at 1-, 3- and 5-year were 0.718, 0.784 and 0.767. The performance of the risk model was validated with GSE25066 and GSE55348. It’s showed that the risk scores of HPBC who were resistant to trastuzumab were significantly higher than those of patients who were sensitive to trastuzumab. The results indicated that the levels of immune checkpoints expression (such as PD-1, CTLA4 and TIGIT) and immune infiltration were higher in low-risk group than in high-risk group. The combined model showed better prognostic prediction accuracy compared to the clinical model or gene signature alone (1-year AUC=0.910;3-year AUC=0.832;5-year AUC=0.882). Conclusion: The immune gene-based risk profile and combined prognostic model in this study may hold promise for clinical use in predicting the prognosis and treatment efficacy of HPBC patients. figure3. Construction of HPBC-IRGs signature based prognostic model. Citation Format: Xiaofen Li, Wenfen Fu, Yushuai Yu, Jie Zhang, Chuangui Song. Clinical significance and immune landscape analyses of the immune related genes based prognostic signature for HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-10.

Does excess body weight accelerate immune aging?

BackgroundOverweight and obesity in older adults increase the risk of a range of comorbidities by sustaining chronic inflammation and thus enhancing immunosenescence. This study aimed to assess whether excess body mass affected disproportion in T lymphocytes. Therefore, the study was designed to explain whether excess body mass in older individuals affected the disproportion in numbers of T lymphocytes and whether anthropometric indices and immune risk profile expressed as CD4/CD8 ratio are diagnostically useful in the analysis of immunosenescence. Materials & methodsOne hundred three individuals aged 73.6 ± 3.1 years were allocated to the normal body mass (body mass index (BMI) 18.5–24.9 kg/m2,n = 39), the pre-obesity (BMI 25.0–29.9 kg/m2, n = 44) or the obesity (BMI ≥30.0 kg/m2, n = 20) group, based on WHO recommendations. Details on the subjects' medical history and lifestyle were obtained by health questionnaire. Anthropometric analysis was performed by bioelectrical impedance method, biochemical analysis was made by the automatic analyzer and ELISA immunoassays, and T and B lymphocyte counts were determined by eight-parameter flow cytometry. Additionally, visceral adiposity index, body adiposity index (BAI), and body shape index (ABSI) were evaluated based on body circumference, BMI and lipid-lipoprotein profile measurements. ResultsThe highest percentage of CD3+CD4+ T lymphocytes (59.4 ± 12.6 %) and the lowest CD3+CD8+ T lymphocytes (31.6 ± 10.0 %) were noted in patients the obesity group. The highest cut-off value of 1.9 for CD4/CD8 ratio was recorded in the normal body mass vs pre-obesity model. CD4/CD8 ratio > 2.5 was recorded in >20 % of our pre-obesity and obesity groups while 64.5 % of the normal body mass group had CD4/CD8 ratio < 1. High diagnostic usefulness was demonstrated for both BAI and lipid accumulation product (LAP) (AUC values of ~0.800 and ~ 0.900 respectively) in three models: normal body mass vs pre-obesity, normal body mass vs obesity, and pre-obesity vs obesity. ConclusionThe odds ratios (OR) for CD4/CD8 ratio in the normal body mass vs obesity model (OR = 16.1, 95%CI 3.8–93.6) indicated a potential diagnostic value of T lymphocytes for clinical prognosis of immune aging in relation to excess body weight in older adults. High values of AUC obtained for the following models: CD4/CD8 + BAI (AUC = 0.927), CD4/CD8 + LAP (AUC = 1.00), CD4/CD8 + ABSI (AUC = 0.865) proved to provide excellent discrimination between older adults with obesity and with normal body mass.

Unraveling the Immune Signature of Herpes Zoster: Insights Into the Pathophysiology and Human Leukocyte Antigen Risk Profile.

The varicella-zoster virus (VZV) infects >95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and individuals who are immunocompromised. However, HZ can occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in patients with HZ using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ human leukocyte antigen association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the major histocompatibility complex locus for HZ development, identifying 5 protective and 4 risk human leukocyte antigen alleles. This demonstrates that HZ susceptibility is largely governed by variations in the major histocompatibility complex. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.

Immune Profile and Body Composition of Independent Oldest Old: The Longevous Project

Introduction: Immunosenescence is associated with changes in lymphocyte function, thymus atrophy, and a chronic inflammatory process referred to as “inflammaging,” which may in part be linked to eating disorders. Objective: The aim of the study was to determine the prevalence rate of immunological alterations, including immune risk profile (IRP), and their association with body composition in the oldest old individuals. Methods: A cross-sectional study of 201 older adults aged 80 years and over, able to walk unaided, with no cognitive or immunological impairment, and with no serious diseases was conducted. Blood samples were collected between 2012 and 2014 during the morning period, and the following tests were conducted: urea, creatinine, hemogram, fasting glucose, glycated hemoglobin, transferrin, albumin, 25-OH vitamin D, and high-sensitivity CRP. Plasma cytokines were measured and mononuclear cell counts were performed by flow cytometry. Anthropometric measurements and densitometry using dual-energy X-ray absorptiometry (DXA) were performed to assess body composition. Results: Mean age was 84.4 ± 3.7 years, and the numbers of T cells were CD4, 784.0 cell/µL; CD8, 371.0 cell/µL; and CD4/CD8, 2.4. The rate of CD4/CD8 <1 (IRP) was 9.4%, CD4/CD8 1–5 was 85.6%, while CD4/CD8 >5 was only 5.5%. CRP, tumor necrosis factor, IL1, IL4, IL6, and IL10 variables showed a high coefficient of variation but low mean values of 1.1 ± 3.1 mg/L for CRP (reference range <3 mg/L) and 3.9 ± 5.0 pg/mL for IL6 (reference range <7.0 pg/mL). The same pattern was found for all other inflammatory variables assessed, characterizing a population whose values indicated low level of inflammation, considering age. Lean mass, as measured by DXA, was higher in men than in women, while the inverse was found for fat % (p < 0.001). A positive association between CRP values and DXA fat % (p value: 0.007, r: 0.49) and a negative association between CRP values and DXA lean mass (p value: 0.046, r:–0.37) was observed. Conclusion: In the independent oldest old, IRP rate proved low and high-sensitivity CRP was shown to be associated with body composition.

Combined Immune Checkpoint Inhibitors, Immunotherapy with Picibanil-based Intraperitoneal Imiquimod, and Chemotherapy in Cases of Advanced Cervical Cancer and Failure of Concurrent Chemoradiation Therapy

This is a case of cervical cancer stage IIB according to the International Federation of Obstetrics and Gynecology Staging who initially presented with abnormal vaginal bloody discharge noted in August 2018. A cervical biopsy showed poorly differentiated squamous cell carcinoma, and pelvic magnetic resonance imaging revealed a 4.3-cm cervical mass involving the anterior lip, upper third of the vagina, and right parametrium without nodal or distant lesions. Although she underwent concurrent chemoradiotherapy, a residual cervical tumor was noted in April 2019. She then underwent salvage radical hysterectomy, bilateral pelvic lymph node dissection, and hyperthermic intraperitoneal chemotherapy with cisplatin in May 2019, followed by immunotherapy (picibanil-based intraperitoneal imiquimod), immune checkpoint inhibitors (pembrolizumab, atezolizumab, ipilimumab, and nivolumab), and concurrent chemoradiotherapy until March 2020. The immune risk profile showed T cell proliferation and alteration of Th1/Th2 activation after immunotherapy and immune checkpoint inhibitor therapy. There was significant increase in natural killer (NK) T cells (3.9-fold) and CD4+CD25 (4.25-fold). CD3, CD4, CD8, CD19, CD8+CD28−, and CD4/CD8 cells were increased, while CD2+CD279+ and NK cells were decreased. She received eight cycles of adjuvant chemotherapy (cisplatin, paclitaxel) and bevacizumab in June 2020 for local tumor recurrence in the pelvis which was found in April 2020. Unfortunately, she died in November 2020 due to septic shock.

Pre-Existing Hypertension Is Related with Disproportions in T-Lymphocytes in Older Age.

Age-related immune deficiencies increase the risk of comorbidities and mortality. This study evaluated immunosenescence patterns by flow cytometry of naïve and memory T cell subpopulations and the immune risk profile (IRP), expressed as the CD4/CD8 ratio and IgG CMV related to comorbidities. The disproportions in naïve and memory T cells, as well as in the CD4/CD8 ratio, were analysed in 99 elderly individuals (71.9 ± 5.8 years) diagnosed with hypertension (n = 51) or without hypertension (n = 48), using an eight-parameter flow cytometer. The percentage of CD4+ T lymphocytes was significantly higher in hypertensive than other individuals independently from CMV infections, with approximately 34% having CD4/CD8 > 2.5, and only 4% of the elderly with hypertension having CD4/CD8 < 1. The elderly with a normal BMI demonstrated the CD4/CD8 ratio ≥ 1 or ≤ 2.5, while overweight and obese participants showed a tendency to an inverted CD4/CD8 ratio. CD4/CD8 ratio increased gradually with age and reached the highest values in participants aged >75 years. The decline in CD4+ naïve T lymphocytes was more prominent in IgG CMV+ men when compared to IgG CMV+ women. The changes in naïve and memory T lymphocyte population, CD4/CD8, and CMV seropositivity included in IRP are important markers of health status in the elderly that are dependent on hypertension.

Obesity Increases Gene Expression of Markers Associated With Immunosenescence in Obese Middle-Aged Individuals.

Recently, it has been argued that obesity leads to a chronic pro-inflammatory state that can accelerate immunosenescence, predisposing to the early acquisition of an immune risk profile and health problems related to immunity in adulthood. In this sense, the present study aimed to verify, in circulating leukocytes, the gene expression of markers related to early immunosenescence associated with obesity and its possible relationships with the physical fitness in obese adults with type 2 diabetes or without associated comorbidities. The sample consisted of middle-aged obese individuals (body mass index (BMI) between 30-35 kg/m²) with type 2 diabetes mellitus (OBD; n = 17) or without associated comorbidity (OB; n = 18), and a control group of eutrophic healthy individuals (BMI: 20 - 25 kg/m²) of same ages (E; n = 18). All groups (OBD, OB and E) performed the functional analyses [muscle strength (1RM) and cardiorespiratory fitness (VO2max)], anthropometry, body composition (Air Displacement Plethysmograph), blood collections for biochemical (anti-CMV) and molecular (gene expression of leptin, IL-2, IL-4, IL-6, IL-10, TNF-α, PD-1, P16ink4a, CCR7, CD28 and CD27) analyses of markers related to immunosenescence. Increased gene expression of leptin, IL-2, IL-4, IL-10, TNF-α, PD-1, P16ink4a, CCR7 and CD27 was found for the OBD and OB groups compared to the E group. Moreover, VO2max for the OBD and OB groups was significantly lower compared to E. In conclusion, obesity, regardless of associated disease, induces increased gene expression of markers associated with inflammation and immunosenescence in circulating leukocytes in obese middle-aged individuals compared to a eutrophic group of the same age. Additionally, increased adipose tissue and markers of chronic inflammation and immunosenescence were associated to impairments in the cardiorespiratory capacity of obese middle-aged individuals.

Immunosenescence profiles are not associated with muscle strength, physical performance and sarcopenia risk in very old adults: The Newcastle 85+ Study

Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85+ Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 (‘Senescent-like phenotype’, n = 421), and Cluster 2 (‘Less senescent-like phenotype’, n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of CD4 and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower CD4/CD8 ratio, CMV+), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.

Immunological aging and clinical consequences

Immunosenescence is defined as the changes in the immune system associated with age. It is a progressive and irreversible process involving a decrease in the number of naïve T and B cells, NK cells cytotoxic and activity, and disruption of pro and anti-inflammatory balance by altering the production of IL-2, -4, -6, -10, -10, TNF-α, interferon γ and others. With age there is an increase in autoimmunity and generalized inflammation with simultaneous immunodeficiency, which results in greater susceptibility to infectious diseases, a decrease in reactivity to prophylactic vaccinations, the incidence of autoimmune diseases, and increased risk of infectious injury complications, exacerbation of symptoms of chronic diseases and an insufficient response to the presence of cells cancer. For years, based on the analysis of the frequency of viral and bacterial infections, immunological indicators and inflammation, attempts have been made to develop the immune risk profile (IRP) and effective methods of preventing disorders of the immune system and prolonging the functional capacity of the elderly.

Accelerated immune aging was correlated with lupus-associated brain fog in reproductive-age systemic lupus erythematosus patients.

Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57+ or loss of CD28 expression), of naïve T cells (CD4+ CD45RA+ and CD8+ CD45RA+ ), memory T cells (CD4+ CD45RO+ and CD8+ CD45RO+ ), and antigen-experienced T cells (CD4+ KLRG1+ and CD8+ KLRG1+ ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P=.005 and P=.000) and MOCA (P=.017 and P=.000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P=.046). There was a negative correlation between memory CD4+ CD45RO+ T cells with recall and visuospatial domain (R=-0.204, P=.039 and R=-0.250, P=.033; respectively), and negative correlation between CD8+ CD28- T cells with recall and attention domain (R=-0.249, P=.027 and R=-0.145, P=.048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.

NK Cells Contribute to the Immune Risk Profile in Kidney Transplant Candidates.

Background: A previously proposed immune risk profile (IRP), based on T cell phenotype and CMV serotype, is associated with mortality in the elderly and increased infections post-kidney transplant. To evaluate if NK cells contribute to the IRP and if the IRP can be predicted by a clinical T cell functional assays, we conducted a cross sectional study in renal transplant candidates to determine the incidence of IRP and its association with specific NK cell characteristics and ImmuKnow® value.Material and Methods: Sixty five subjects were enrolled in 5 cohorts designated by age and dialysis status. We determined T and NK cell phenotypes by flow cytometry and analyzed multiple factors contributing to IRP.Results: We identified 14 IRP+ [CMV seropositivity and CD4/CD8 ratio < 1 or being in the highest quintile of CD8+ senescent (28CD–/CD57+) T cells] individuals equally divided amongst the cohorts. Multivariable linear regression revealed a distinct IRP+ group. Age and dialysis status did not predict immune senescence in kidney transplant candidates. NK cell features alone could discriminate IRP– and IRP+ patients, suggesting that NK cells significantly contribute to the overall immune status in kidney transplant candidates and that a combined T and NK cell phenotyping can provide a more detailed IRP definition. ImmuKnow® value was negatively correlated to age and significantly lower in IRP+ patients and predicts IRP when used alone or in combination with NK cell features.Conclusion: NK cells contribute to overall immune senescence in kidney transplant candidates.

CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age.

Natural killer cells lacking expression of CD56 (CD56neg NK cells) have been described in chronic HIV and hepatitis C virus infection. Features and functions of CD56neg NK cells in the context of latent infection with CMV and / or EBV with age are not known. In a cohort of healthy donors >60 years of age, we found that co-infection with CMV and EBV drives expansion of CD56neg NK cells. Functionally, CD56neg NK cells displayed reduced cytotoxic capacity and IFN-γ production, a feature that was enhanced with CMV / EBV co-infection. Further, the frequency of CD56neg NK cells correlated with accumulation of end-stage-differentiated T cells and a reduced CD4 / CD8 T cell ratio, reflecting an immune risk profile. CD56neg NK cells had a mature phenotype characterized by low CD57 and KIR expression and lacked characteristics of cell senescence. No changes in their activating NK cell receptor expression, and no upregulation of the negative co-stimulation receptors PD-1 or TIM-3 were observed. In all, our data identify expansion of dysfunctional CD56neg NK cells in CMV+EBV+ elderly individuals suggesting that these cells may function as shape-shifters of cellular immunity and argue for a previously unrecognized role of EBV in mediating immune risk in the elderly.

Low DNA damage in peripheral lymphocytes of healthy elderly individuals with inverted CD4:CD8 ratio

The aim of this study was to evaluate the DNA damage in peripheral lymphocytes and the frequencies of CD8+ T cells expressing CD25, CD28 and CD45ro in aged individuals with inverted CD4:CD8 ratio. Blood samples of elderly individuals (aged >65) with normal CD4:CD8 ratio (n = 8) and inverted CD4:CD8 ratio (n = 8) were collected to identify the expression of CD25+, CD28+ and CD45ro+ in CD8+ T cells. DNA damage index was evaluated by the alkaline comet assay which was performed in lymphocytes treated with different concentrations of methyl methanesulfonate (MMS) (control non-treatment, 2 × 10−5 M, 4 × 10−5 M) for 1, 2 or 24 h. Elderly individuals with inverted CD4:CD8 ratio presented low frequency of CD8+ CD28+. Moreover, low DNA damage was observed in lymphocytes of elderly with inverted CD4:CD8 ratio in different doses of MMS. Aged individuals with inverted CD4:CD8 ratio presented lower DNA damage events in peripheral lymphocytes, suggesting a resistance for cell death in T cells of individuals with immune risk profile.

Collateral damage: Molecular aging and p16INK4a senescence protein in testicular cancer survivors treated with chemotherapy.

548 Background: Cytotoxic chemotherapy can cure patients with advanced germ cell tumors. Nevertheless, cancer treatment may induce cellular senescence and accelerate molecular aging. The aging process implies an increase of cells expressing p16INK4a and changes in lymphocyte subpopulations. Our aim was to study the potential induction of premature immunosenescence in testicular cancer patients exposed to chemotherapy. Methods: Case-control study of testicular cancer survivors (TCS) treated with chemotherapy (≥3 BEP cycles, disease-free ≥ 3 months) matched by age with healthy controls. Peripheral blood mononuclear cells were isolated, and lymphocyte subpopulations were analyzed by flow cytometry. p16INK4a expression was measured using real-time polymerase chain reaction, and the 2-ΔΔCt method was used for the p16INK4a expression analysis. Groups were compared with Mann-Whitney U test. Results are expressed as median (IQR) unless otherwise indicated. Results: We included 15 cases and 15 controls. Mean age 32.5 yo (24-54), mean time since last chemo 49.5 months (3-192). TCS had a lower percentage of CD3+ (62 (57-68) vs 72 (65-82) p = 0.026) and CD4+ (35 (27-41) vs 42 (38-53) p = 0.013) cells in total lymphocytes. TCS also had a lower % of naïve CD4+ (32 (15-44) vs 39 (32-55) p = 0.041), CD4+CD28+ (90 (85-97) vs 98 (95-99) p = 0.029) and CD8+ naïve (15 (8-26) vs 27 (22-42) p = 0.023) cells. TCS had an increased % of memory CD4+ (18 (13-26) vs 9 (6-11) p = 0.001) and memory CD19+ B cells (76 (62-88) vs 70 (64-79) p = 0.004). The relative expression of p16INK4a in CD3+ cells was higher in TCS compared to controls (1.29±0.36 vs 0.85±0.54; p = 0.035). Conclusions: TCS showed an increase in the expression of the aging biomarker p16INK4a and a lymphocyte phenotype associated with immunosenescence; characterized by a decrease in naïve cells, and concomitant increment of memory and CD28- cells. This phenomenon is believed to contribute to the development of an immune risk profile in the elderly, associated with an increased rate of infections and a diminished effect of vaccines. This is the first time this finding is reported in TCS. Further studies are warranted to define the clinical implications of this alteration.

Immune parameters associated with mortality in the elderly are context-dependent: lessons from Sweden, Holland and Belgium.

The pioneering Swedish OCTO/NONA-Immune longitudinal studies led by Anders Wikby in Jönköping in the 1990s established a cluster of simple baseline immune parameters associated with excess mortality in 85year-old non-institutionalized individuals over 2, 4 and 6-year follow-up. We dubbed this cluster the "Immune Risk Profile" (IRP) consisting of poor proliferative responses of peripheral blood mononuclear cells to T cell mitogens, accumulations of CD8+ CD28- T-cells resulting in an inverted CD4:8 ratio, decreased amounts of B-cells, and seropositivity for Cytomegalovirus (CMV). The concept of the IRP has since been applied by others to many different populations in different circumstances and at different ages, but in general without specifically establishing whether the same risk factors were relevant in the tested subjects. However, our own later studies showed that risk factors in aged populations from The Netherlands and Belgium were markedly different, indicating that the IRP cannot simply be transferred between populations. Moreover, there was a striking sex difference in the Belgian study, which was the only one large enough to include sufficient numbers of old men. The reasons for these marked differences between populations which one might have assumed a priori to be quite similar to one another are not clear, and many candidates can be speculated upon, but the important lesson is that there is a marked context-dependency of immune biomarkers of ageing, suggesting that IRPs cannot be assumed to be identical in different populations.

The role of gender and labour status in immunosenescence of 65+ Polish population

Women are living longer than men and it seems that one of the reasons could be better immune system of females. In Poland, contrary to many European countries, women retire earlier than men, namely at 60 and 65, respectively. We asked the question how the gender and labour status were interconnected with some immunological parameters included in the so called immune risk profile (IRP), such as CD4+/CD8+ ratio, percentage of CD8+CD28−, and NK, and the level of circulating cytokines. A total of 92 men and 100 women past the retirement age, namely 65–74 years old, still working or not, were examined. We have found statistically significant lower percentage of CD8+CD28− cells and non-statistically significant higher CD4+/CD8+ ratio in women, whereas the percentage of NK was higher in men. Moreover, the percentage of CD8+CD28− cells was negatively correlated with the CD4+/CD8+ ratio and the concentration of IL8 was positively correlated with the concentration of IL10 both in men and women. In men, the level of IL10 was higher than in women. Altogether, we found that gender, but not labour status, influences immunosenescence of the examined population of 65–74 years old Polish people.

Pre-transplant end-stage renal disease-related immune risk profile in kidney transplant recipients predicts post-transplant infections.

End-stage renal disease (ESRD) is associated with premature aging of the T-cell system. Nevertheless, the clinical significance of pre-transplant ESRD-related immune senescence is unknown. We studied whether immune risk phenotype (IRP), a typical feature of immune senescence, may affect post-transplant infectious complications. A total of 486 patients were prospectively studied during the first year post transplant. IRP was defined as positive cytomegalovirus serology with at least 1 of the following criteria: CD4/CD8 ratio <1 and/or CD8 T-cell count >90th percentile. We found that 47 patients (9.7%) had pre-transplant IRP. IRP+ patients did not differ from IRP- patients for any clinical characteristics, but exhibited more pronounced immune senescence. Both opportunistic infections (43% vs. 6%, P < 0.001) and severe bacterial infection (SBI) (40% vs. 25%, P = 0.028) were more frequent in IRP(+) patients. In multivariate analysis, IRP was predictive of both opportunistic infection (hazard ratio [HR] 2.97 [95% confidence interval {CI} 1.53-5.76], P = 0.001), and SBI (HR 2.33 [95% CI 1.34-3.92], P = 0.008). Acute rejection rates were numerically much lower in IRP+ patients. A total of 418 patients (86%) had biological evaluation 1 year post transplant. Among 41 IRP+ patients, 35 (85%) remained IRP+ 1 year post transplant. Pre-transplant IRP is associated with an increased risk of post-transplant infection.

Cytomegalovirus Infection Minimally Affects the Frequencies of B-Cell Phenotypes in Peripheral Blood of Younger and Older Adults

Background: An accumulation of late-differentiated CD8+ T-cells together with fewer B-cells and seropositivity for cytomegalovirus (CMV) characterises an ‘immune risk profile' associated with mortality in elderly people and represents one of the hallmarks of ‘immunosenescence'. Objectives: While differences in memory T-cell phenotypes between young and old people have been intensively studied, and the role of CMV is well-accepted as a driving force in this regard, the impact of CMV on B-cells, if any, has been relatively neglected thus far. Methods: Here, we avail ourselves of blood samples from participants of the Berlin Aging Study II (BASE-II) to compare peripheral blood B-cell differentiation phenotypes of 140 age- and gender-matched CMV-seronegative or -seropositive adults aged between 24 and 85 years using multicolour flow cytometry analysis. Results: We found that the frequencies of naïve B-cells within the CD19+ population were not significantly different in younger and older CMV-seronegative people. This was also true in CMV-seropositive subjects. The frequencies of late-differentiated B-cells were also not different in CMV-negative elderly and young. However, in marked contrast to the T-cell compartment, this was also true for late differentiated B-cells. Within age groups, the most marked differences in the distribution of B-cell phenotypes were between CMV-seronegative and -seropositive subjects, for both genders. Conclusion: These results emphasize the importance of including CMV serostatus in the analysis of immune signatures. Because the proportion of the population infected with CMV increases with age, the effect of CMV rather than age could confound analyses seeking age-associated changes to human immunity.

Humoral response to influenza vaccination in relation to pre-vaccination antibody titres, vaccination history, cytomegalovirus serostatus and CD4/CD8 ratio

Background Annual vaccination against influenza virus is generally recommended to elderly and chronically ill, but the relative importance of factors influencing the outcome is not fully understood. Methods In this study of 88 individuals all aged 69 years, the increase in haemagglutinin-inhibiting (HI) antibodies to trivalent inactivated influenza vaccine was correlated with HI titres before vaccination, prior vaccinations against influenza, cytomegalovirus serostatus and, as an estimate of immune risk profile, the ratio between CD4 + and CD8 + T cells. Results Vaccine responses were impaired by high pre-existing HI antibody titres. For influenza B repeated vaccinations and an inverse CD4/CD8 ratio had a negative impact on the vaccine response. Cytomegalovirus seropositivity had no apparent effect on HI titres before or after vaccination. Conclusions It is concluded that both pre-existing HI antibodies and previous vaccinations to influenza may influence the humoral response to influenza vaccination and that a CD4/CD8 ratio < 1 may indicate an impaired ability to respond to repeated antigenic stimulation.

Promising Tumor Remission After Immunotherapy for Late Relapse of Locally Advanced Cervical Adenocarcinoma Revealed by [18F] Fluoro-2-Deoxy-DGlucose Positron Emission Tomography

The prognosis of patients with metastatic cervical cancer is poor, with a median survival of 8-13 months. Treatment with chemotherapeutic drugs alone is rarely curative. In the past few years, the development of immunotherapy, targeted therapy, angiogenesis inhibitors, and tyrosine kinase inhibitors has provided better treatment choices for patients with metastatic cervical cancer. A 52-year-old woman was diagnosed on July 2001, with locally advanced adenocarcinoma of cervix, stage IIb. She underwent concurrent chemoradiotherapy resulting in complete remission for over 10 years. Unfortunately, she was found to have a late relapse of cervical adenocarcinoma with liver metastases (segments 7 and 8) on June 2013. She underwent segmental hepatectomy and cholecystectomy and was transferred to our gynecologic oncology service for standard chemotherapy with immunotherapy based on her immune risk profile (IRP). Immunomodulatory agents, including picibanil (OK-432), interferon-alpha, celecoxib (cyclooxygenase-2 inhibitor), thymalfasin, and aldesleukin (IL-2) were given. Approximately 20 months later, spleen metastasis was suspected by [18F] fluoro-2-deoxy-D-glucose positron emission tomography. The patient underwent gasless laparoscopic intraperitoneal treatment with immunomodulatory agent celecoxib (cyclooxygenase-2 inhibitor) and intraperitoneal immunoviral therapy to create host immunosurveillance for consolidation therapy. Three months later, there was complete remission of the metastatic splenic nodule on repeat imaging. Our case demonstrates the dramatic promise of immunomodulatory therapy to induce complete remission of a metastatic cancer nodule. This case suggests the potential value of immunotherapy to augment host immunosurveillance to improve survival of metastatic cervical cancer.