Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab.

BACKGROUND: Immunotherapy has changed the paradigm of treating non-small cell lung cancer (NSCLC). But, selecting patients who will achieve long-term benefits from treatment remains unsatisfactory. Here, we investigated the possible use of the soluble form of CD8 antigen (sCD8) in predicting durable disease control after PD-1/PD-L1 blockade. CD8 is a marker of the cytotoxic T lymphocytes. Its soluble form (sCD8) is secreted under activation of the immune system but also has immunosuppressive properties. The data about serum sCD8 in patients dosed with anti-PD-1/PD-L1 drugs are lacking. METHODS AND RESULTS: We included 42 NSCLC patients and collected samples at baseline and for the first 3 months of atezolizumab immunotherapy. The serum sCD8 concentrations were measured with the ELISA kit and correlated with treatment outcomes. Patients with durable (≥ 12 months) disease control presented lower serum sCD8 than those without long-term benefits. The sCD8 levels measured at the end of cycle 2 (sCD8.2) were the earliest time point that successfully differentiated patients (3.76 vs. 9.68 ng/mL, respectively, p < 0.001). Individuals with low sCD8.2 (≤ 4.09 ng/mL) presented longer progression-free survival (HR = 0.061, p < 0.001) and overall survival (HR = 0.104, p < 0.05) compared to individuals with high sCD8.2 (median values unreached vs. 4.4 months and 14.4 months for PFS and OS, respectively). CONCLUSIONS: Serum sCD8 could be an early biomarker of durable disease control after anti-PD-L1 treatment. Higher sCD8 in patients with worse outcomes could suggest the inhibitory effect of sCD8 on cytotoxic T-cells activation.

Serum CD4 Is Associated with the Infiltration of CD4+T Cells in the Tumor Microenvironment of Gastric Cancer.

Serum CD4, CD8, and CD19 are markers of systemic inflammation. However, there is little evidence on the influence of inflammation on the tumor microenvironment and the prognostic indicators of gastric cancer (GC). In this study, two hundred and eight patients who underwent radical gastrectomy for GC were included. Preoperative peripheral blood samples were used to analyze Serum CD4, CD8, and CD19. The optimal cutoff levels for CD4, CD8, and CD19 were defined by receiver operating characteristic curve analysis (CD4 = 38.85%, CD8 = 14.35%, and CD19 = 7.40%). The areas with specific CD4+T cells, CD8+T cells, and CD19+B cells within the tumor microenvironment were measured in paraffin sections by immunohistochemistry and analyzed by Image-Pro Plus. 94 patients had low CD4, and 124 patients had high CD4 levels. 31 patients had low CD8, and 187 patients had high CD8 levels. 64 patients had low CD19, and 154 patients had high CD19 levels. Infiltration of CD4+T cells was associated with serum CD4 (P < 0.001). Serum CD4 and CD19 and the infiltration of CD4+T cells, CD8+T cells, and CD19+B cells were significant in predicting the prognosis of GC. Low CD4 level, infiltration of CD8+T cells, and high infiltration of CD4+T cells and CD19+B cells were correlated with worse overall survival in multivariate analysis. Collectively, our results provide evidence that serum CD4 is associated with the infiltration of CD4+T cells in the tumor microenvironment, which indicates the prognostic value of systemic inflammation in GC.

Inflammation Mediates Exercise Effects on Fatigue in Patients with Breast Cancer.

PURPOSE: The randomized controlled OptiTrain trial showed beneficial effects on fatigue after a 16-wk exercise intervention in patients with breast cancer undergoing adjuvant chemotherapy. We hypothesize that exercise alters systemic inflammation and that this partially mediates the beneficial effects of exercise on fatigue. METHODS: Two hundred and forty women scheduled for chemotherapy were randomized to 16 wk of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). In the current mechanistic analyses, we included all participants with >60% attendance and a random selection of controls (RT-HIIT = 30, AT-HIIT = 27, UC = 29). Fatigue (Piper Fatigue Scale) and 92 markers (e.g., interleukin-6 [IL-6] and tumor necrosis factor α [TNF-α]) were assessed at baseline and postintervention. Mediation analyses were conducted to explore whether changes in inflammation markers mediated the effect of exercise on fatigue. RESULTS: Overall, chemotherapy led to an increase in inflammation. The increases in IL-6 (pleiotropic cytokine) and CD8a (T-cell surface glycoprotein) were however significantly less pronounced after RT-HIIT compared with UC (-0.47, 95% confidence interval = -0.87 to -0.07, and -0.28, 95% confidence interval = -0.57 to 0.004, respectively). Changes in IL-6 and CD8a significantly mediated the exercise effects on both general and physical fatigue by 32.0% and 27.7%, and 31.2% and 26.4%, respectively. No significant between-group differences in inflammatory markers at 16 wk were found between AT-HIIT and UC. CONCLUSIONS: This study is the first showing that supervised RT-HIIT partially counteracted the increase in inflammation during chemotherapy, i.e., IL-6 and soluble CD8a, which resulted in lower fatigue levels postintervention. Exercise, including both resistance and high-intensity aerobic training, might be put forward as an effective treatment to reduce chemotherapy-induced inflammation and subsequent fatigue.

Differences in biomarkers of inflammation and immune responses in chronic smokers and moist snuff users.

BACKGROUND: Cigarette smoking is a major risk factor for cancer and other diseases. While smoking induces chronic inflammation and aberrant immune responses, the effects of smokeless tobacco products (STPs) on immune responses is less clear. Here we evaluated markers related to immune regulation in smokers (SMK), moist snuff consumers (MSC) and non-tobacco consumers (NTC) to better understand the effects of chronic tobacco use. MATERIALS AND METHODS: Several markers associated with immune regulation were measured in peripheral blood mononuclear cells (PBMCs) from SMK (n = 40), MSC (n = 40), and NTC (n = 40) by flow cytometry. RESULTS: Relative to NTC, seven markers were significantly suppressed in SMK, whereas in MSC, only one marker was significantly suppressed. In a logistic regression model, markers including granzyme B+ lymphocytes, perforin+ lymphocytes, granzyme B+ CD8+T cells, and KLRB1+ CD8+ T cells remained as statistically significant predictors for classifying the three cohorts. Further, cell-surface receptor signaling pathways and cell-cell signaling processes were downregulated in SMK relative to MSC; chemotaxis and LPS-mediated signaling pathways, were upregulated in SMK compared to MSC. A network of the tested markers was constructed to visualize the immunosuppression in SMK relative to MSC. CONCLUSION: Moist snuff consumption is associated with significantly fewer perturbations in inflammation and immune function biomarkers relative to smoking. IMPACT: This work identifies several key immunological biomarkers that differentiate the effects of chronic smoking from the use of moist snuff. Additionally, a molecular basis for aberrant immune responses that could render smokers more susceptible for infections and cancer is provided.

Characterization of immunoreactivity with whole-slide imaging and digital analysis in high-grade serous ovarian cancer.

Ovarian cancer is the most lethal of gynecological cancers with 5-year survival rate of ca. 45%. The most common histologic subtype is high-grade serous carcinoma, which typically is presented with advanced stage and development of chemoresistance. Therefore, new treatment options, including immunotherapies, are needed. Understanding the features of the immune cell populations in the tumor microenvironment is essential for developing personalized treatments and finding predictive biomarkers. Digital image analysis may enhance the accuracy and reliability of immune cell infiltration assessment in the tumor microenvironment. The aim of this study was to characterize tumor microenvironment in a retrospective cohort of high-grade serous carcinoma samples with whole-slide imaging and digital image analysis. Formalin-fixed paraffin-embedded high-grade serous carcinoma tumor tissue samples (n = 67) were analyzed for six immunohistochemical stainings: CD4, CD8, FoxP3, granzyme B, CD68, and CD163. The stained sample slides were scanned into a digital format and assessed using QuPath 0.1.2 and ImageJ software. Staining patterns were associated with clinicopathological data. The higher numbers of intraepithelial CD8+, CD163+, and granzyme B+ immune cells were associated with survival benefit when analyzed individually, while high levels of both CD8+ and granzyme B+ tumor-infiltrating lymphocytes were an independent prognostic factor in the Cox multivariate regression analysis (median progression-free survival; hazard ratio = 0.287, p = 0.002). Specimens taken after administration of neoadjuvant chemotherapy presented with lower FoxP3+ tumor-infiltrating lymphocyte density (Fisher's exact test, p = 0.013). However, none of the studied immunomarkers was associated with overall survival or clinical factors. Tumors having high amount of both intraepithelial CD8+ and granzyme B+ tumor-infiltrating lymphocytes showed better progression-free survival, possibly reflecting an activated immune state in the tumor microenvironment. The combined positivity of CD8 and granzyme B warrants further investigation with respect to predicting response to immune therapy. Neoadjuvant chemotherapy may have an effect on the tumor microenvironment and therefore on the response to immuno-oncologic or chemotherapy treatments.

CD4/CD8 ratio is a prognostic factor in IgG nonresponders among peptide vaccine-treated ovarian cancer patients.

The identification of useful biomarkers is an urgent issue in cancer treatment, particularly for immunotherapy, as only some patients experience benefits from this treatment. The early induction of the IgG response has been reported as a useful biomarker of favorable prognosis for cancer patients treated with a personalized peptide vaccination, but a portion of these patients (IgG nonresponders) fail to achieve an early induction of IgG response yet experience long-term survival. It is thus necessary to identify other biomarkers of favorable prognosis among these patients. Here we report the usefulness of classical T-cell markers (ie, the CD8 content and the CD4/CD8 ratio in peripheral blood) in IgG nonresponders among advanced or recurrent ovarian cancer patients treated with a personalized peptide vaccination. Among IgG nonresponders (n = 25), the overall survival (OS) of the increased-CD8 group (n = 7) was significantly longer than that of the decreased-CD8 group (n = 18; P = .018), and the OS of the patients with a decreased CD4/CD8 ratio (n = 10) was significantly longer than that of the patients with an increased ratio (n = 15; P = .0055). Thus, an increased content of CD8 and a decreased CD4/CD8 ratio are each favorable prognosis markers in IgG nonresponders treated with a personalized peptide vaccination.

Double Positive CD4+CD8+ T Cells Are Enriched in Urological Cancers and Favor T Helper-2 Polarization.

The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4+CD8+ T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (n = 54), prostate (n = 31), and kidney (n = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4highCD8low and CD4+CD8high DP T-cell subsets. Of note, most CD4highCD8low DP T cells show a CD8αα phenotype, whereas CD4+CD8high cells express both CD8α and CD8ß subunits. Functional properties were investigated using ex-vivo generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αß DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4+CD8+ T cells in urological cancers.

Relationship of the Content of Systemic and Endobronchial Soluble Molecules of CD25, CD38, CD8, and HLA-I-CD8 and Lung Function Parameters in COPD Patients.

The definition of new markers of local and systemic inflammation of chronic obstructive pulmonary disease (COPD) is one of the priority directions in the study of pathogenesis and diagnostic methods improvement for this disease. We investigated 91 patients with COPD and 21 healthy nonsmokers. The levels of soluble CD25, CD38, CD8, and HLA-I-CD8 molecules in the blood serum and exhaled breath condensate (EBC) in moderate-to-severe COPD patients during exacerbation and stable phase were studied. An unidirectional change in the content of sCD25, sCD38, and sCD8 molecules with increasing severity of COPD was detected. The correlations between the parameters of lung function and sCD8, sCD25, and sHLA-I-CD8 levels in the blood serum and EBC were discovered in patients with severe COPD. The findings suggest a pathogenetic role of the investigated soluble molecules of the COPD development and allow considering the content of sCD8, sCD25, and sHLA-I-CD8 molecules as additional novel systemic and endobronchial markers of the progression of chronic inflammation of this disease.

CD8+CD28+/CD8+CD28- T cell equilibrium can predict the active stage for patients with inflammatory bowel disease.

BACKGROUND/AIM: The balance of blood CD8+CD28+/CD8+CD28- T cells has been verified to be vital for patients with ulcerative colitis (UC), but their role in inflammatory bowel disease (IBD) remains unknown. This investigation aimed to evaluate the efficiency of the balance in predicting the active stage in IBD patients. METHODS: Fifty-three IBD subjects, including 31 UC and 22 Crohn's disease (CD) patients, were enrolled, and their peripheral blood CD8+CD28+ and CD8+CD28- T cell levels were tested using flow cytometry. The risk factors related to prognosis were compared between UC and CD patients. A 1-year follow-up was performed for all the IBD patients, and the CD8+ T cells and their ratio were compared at the 3rd, 6th, 9th, and 12th months during follow-up. The sensitivity and specificity of the CD8+ T cell level and balance were analyzed through receiver operator characteristic (ROC) curves. The cumulative remission lasting rates (CRLRs) under the different factors were analyzed using the Kaplan-Meier method. RESULTS: Higher prescription rates of immunosuppressants, steroids, probiotics, and biological agents (BAs) were found in CD subjects in comparison to UC subjects (P=0.005, 0.024, 0.034, and 0.001), as was a higher active rate during follow-up (95.5% of CD patients vs 67.7% of UC patients, P=0.035). The CD8+CD28+ T cell level and the CD8+CD28+/CD8+CD28- T cell ratio were significantly higher in UC patients than in CD patients, but the reverse was true for CD8+CD28- T cells during follow-up at the 9th and 12th month (all P<0.05). The diagnostic models of the initial CD8+CD28+ and CD8+CD28- T cell numbers and the CD8+CD28+/CD8+CD28- T cell ratio in predicting the active stage were found to be significant, with areas under the curves (AUCs) of 0.883, 0.098, and 0.913 for UC subjects (with 95% CI: 0.709-0.940, 0.009-0.188, and 0.842-1.003; P=0.001, 0.00, and 0.000) and 0.812, 0.078, and 0.898 for CD subjects (with 95% CI: 0.683-0.957, 0.003-0.158, and 0.837-0.998; P=0.003, 0.00, and 0.000). The cut-off values showed that when the ratios were 1.30 for UC and 1.22 for CD patients, the best sensitivity and specificity were observed, with 91.6% and 89.0% for UC and 88.5% and 85.1% for CD, respectively. The CRLRs were significantly higher in female, non-BA-treated, non-surgical IBD subjects when compared to male, BA-treated, surgical subjects (P=0.031, 0.000, and 0.000). The number of CD8+CD28+ and CD8+CD28- T cells and the CD8+CD28+/CD8+CD28- T cell ratio were correlated with BA treatment and surgery (all P<0.05). CONCLUSION: The CD8+CD28+/CD8+CD28- T cell balance, expected to be a novel immunologic marker, presented a satisfactory efficiency with high sensitivity and specificity in predicting the active stage in UC and CD patients, and the balance was closely related to the use of BAs and surgery.

Positive Epstein-Barr virus detection and mortality in respiratory failure patients admitted to the intensive care unit.

BACKGROUND: Epstein-Barr virus (EBV) infection may induce immune suppression in several ways, which may influence the proper host response to other pathogens and lead to a bad outcome of critically ill patients. METHODS: This was a single-center, retrospective, observational study. All patients admitted to an ICU because of respiratory failure were included. EBV detection from lower respiratory tract (LRT) and serum samples were routinely performed. RESULTS: Twenty-eight consecutive cases who were admitted to the ICU at high-risk for an infection or clinical signs of an infection were included in our study. Among the 28 patients, 15 were LRT-positive for EBV (53.6%), and 8 were seropositive for EBV (28.6%). Among the LRT EBV-positive patients, pneumonia was the main indication for ICU admission (93.3%), and in LRT EBV-negative patients, acute exacerbation of COPD (AECOPD) was another indication for ICU admission (46.2%). The CD3+ T cell count (especially the CD3+CD8+ T cell count) was lower than the normal range in LRT- and serum EBV-positive patients; these count were in the normal range in EBV-negative patients. The ICU mortality was 32.1% for all patients. The mortality rate was significantly higher in patients who were seropositive for EBV than seronegative patients (62.5% vs 20.0%). No differences were shown between any outcome parameters for LRT EBV-positive and -negative patients. CONCLUSIONS: This study showed that EBV DNA is detected in LRT and serum samples of a significant number of ICU patients with respiratory failure, and seropositivity for EBV was associated with mortality. This finding maybe correlated with a low CD3+CD8+ T cell count.

Anti-tumor effects of (1→3)-ß-d-glucan from Saccharomyces cerevisiae in S180 tumor-bearing mice.

(1→3)-ß-d-Glucan from Saccharomyces cerevisiae is a typical polysaccharide with various biological effects and is considered a candidate for the prevention and treatment of cancer in vitro. Research into the function of (1→3)-ß-d-glucan in tumor-bearing animals in vivo, however, is limited. Here, we investigated the effects of (1→3)-ß-d-glucan from S. cerevisiae on S180 tumor-bearing mice and on the immunity of the tumor-bearing host. The molecular mechanisms underlying the observed effects were investigated. (1→3)-ß-d-Glucan was shown to exert anti-tumor effects without toxicity in normal mouse cells. The volume and weight of S180 tumors decreased dramatically following treatment with (1→3)-ß-d-glucan, and treatment with the polysaccharide was furthermore shown to increase the tumor inhibition rate in a dose-dependent manner. Spleen index, T lymphocyte subsets (CD4 and CD8), as well as interleukins (IL)-2, (IL-2, IL-6), and tumor necrosis factor-α were assayed to detect the immunoregulatory and anti-tumor effects after (1→3)-ß-d-glucan intragastrical administration. (1→3)-ß-d-Glucan was shown to significantly potentiate the mouse immune responses by, among other effects, decreasing the ratio of CD4 to CD8. The expression levels of IL-2, IL-6, and TNF-α were also significantly increased by (1→3)-ß-d-glucan. These results suggest that (1→3)-ß-d-glucan enhances the host's immune function during the tumor inhibition process. S180 tumor cells treated with (1→3)-ß-d-glucan also exhibited significant apoptotic characteristics. (1→3)-ß-d-glucan increased the ratio of Bax to Bcl-2 at the translation level by up-regulating Bax expression and down-regulating Bcl-2 expression, resulting in the initiation of cell apoptosis in S180 tumor-bearing mice. Taken together, these results indicate that the anti-tumor effects exerted by (1→3)-ß-d-glucan may be attributed to the polysaccharide's immunostimulating properties and apoptosis-inducing features. Further investigation into these properties and their associated mechanisms will contribute to the development of potent polysaccharide-based anti-tumor agents.

The administration of milk fermented by the probiotic Lactobacillus casei CRL 431 exerts an immunomodulatory effect against a breast tumour in a mouse model.

Antitumour activity is one of the health-promoting effects attributed to probiotics specially analysed from preclinical models, mostly murine. Here, the effect of milk fermented by the probiotic bacterium Lactobacillus casei CRL 431, on a murine breast cancer model was analysed. Mice were fed with milk fermented by Lactobacillus casei or unfermented milk before and after tumour injection. Rate of tumour development, cytokines in serum, IgA, CD4, CD8, F4/80 and cytokines positive cells in mammary glands were determined. Microvasculature in the tumour tissues was monitored. The effect of fermented milk administration after tumour injection was also evaluated. It was observed that probiotic administration delayed or blocked tumour development. This effect was associated to modulation of the immune response triggered by the tumour. The area occupied by blood vessels decreased in the tumours from mice given fermented milk which agrees with their small tumours, and fewer side effects. Finally, it was observed that probiotic administration after tumour detection was also beneficial to delay the tumour growth. In conclusion, we showed in this study the potential of milk fermented by the probiotic Lactobacillus casei CRL431 to stimulate the immune response against this breast tumour, avoiding or delaying its growth when it was preventively administrated and also when the administration started after tumour cells injection.

Expansion of highly differentiated cytotoxic terminally differentiated effector memory CD8+ T cells in a subset of clinically stable kidney transplant recipients: a potential marker for late graft dysfunction.

Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vß repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vß diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.

Peripheral blood CD8αα+CD11c+MHC-II+CD3- cells attenuate autoimmune glomerulonephritis in rats.

In an anti-glomerular basement membrane (GBM) glomerulonephritis (GN) model, GN-resistant Lewis rats naturally recover from early glomerular inflammation. Here we investigated recovery mechanisms for development of a potential immunotherapy for autoimmune GN. Our previous studies suggested that glomeruli-infiltrating leukocytes with a phenotype of CD8αα+CD11c+MHC-II+CD3- (GIL CD8αα+ cells) were responsible for recovery through induction of T-cell apoptosis. Now, we identified peripheral blood CD8αα+CD11c+MHC-II+CD3- cells (PBMC CD8αα+CD3- cells), which shared 9 markers with GIL CD8αα+ cells. Upon incubation, PBMC CD8αα+CD3- cells displayed a morphology resembling that of dendritic cells. Similar to GIL CD8αα+ cells, PBMC CD8αα+CD3- cells were capable of inducing T-cell apoptosis in vitro. Hence, PBMC CD8αα+CD3- cells were likely the precursor of GIL CD8αα+ cells. We next tested their potential in vivo function. PBMC CD8αα+CD3- cells were able to infiltrate inflamed but not normal glomeruli. Isolated PBMC CD8αα+CD3- cells of Lewis rats were transferred into GN-prone Wistar-Kyoto rats at early inflammatory stage (days 17-25). When examined at day 45, both histopathology and blood urea nitrogen/serum creatinine level showed significantly attenuated GN in 80% of cell recipient Wistar-Kyoto rats. Separate experiments verified infiltration of transferred Lewis PBMC CD8αα+CD3- into the glomeruli, accompanied with apoptotic CD4+ T cells in the glomeruli of the recipient Wistar-Kyoto rats. Thus, PBMC CD8αα+CD3- cells of Lewis rats were able to terminate ongoing autoimmune inflammation in the glomeruli.

Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy.

Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are implicated directly in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). In this study we characterize the peripheral blood CD8(+) CD28(-) regulatory T cells (Treg) contribution to the immunoregulatory network in health and in RA. In health, CD8(+) CD28(-) Treg are suppressive but, unlike CD4(+) Treg , they function predominantly through the action of soluble mediators such as interleukin (IL)-10 and transforming growth factor (TGF)-ß. Neutralization of TGF-ß consistently reduced CD8(+) CD28(-) Treg suppressor function in vitro. RA, CD8(+) CD28(-) Treg are increased numerically, but have reduced expression of inducible co-stimulator (ICOS) and programmed death 1 (PD-1) compared to healthy or disease controls. They produce more IL-10 but autologous T cells express less IL-10R. This expression was found to be restored following in-vitro addition of a tumour necrosis factor inhibitor (TNFi). Deficiencies in both the CD8(+) CD28(-) Treg population and reduced sensitivity of the T responder cells impact upon their regulatory function in RA. TNFi therapy partially restores CD8(+) CD28(-) Treg ability in vivo and in vitro, despite the defects in expression of functionally relevant molecules by RA CD8(+) CD28(-) Treg compared to healthy controls. This study places CD8(+) CD28(-) Treg cells in the scheme of immune regulation alongside CD4(+) Treg cells, and highlights the importance of understanding impaired responsiveness to regulation that is common to these suppressor subsets and their restored function in response to TNFi therapy.

The immune signature of CD8(+)CCR7(+) T cells in the peripheral circulation associates with disease recurrence in patients with HNSCC.

PURPOSE: Patients with cancer have an increased frequency of circulating apoptosis-sensitive CD8(+)CCR7(neg) T cells and few CD8(+)CCR7(+) T cells versus normal controls. The functional and clinical significance of this imbalance was investigated using peripheral blood of patients with squamous cell carcinoma of the head and neck (HNSCC). EXPERIMENTAL DESIGN: The frequency of circulating CD8(+) T cells co-expressing CCR7, CD45RO, CD28, and Annexin V (ANXV) was evaluated in 67 patients and 57 normal controls by flow cytometry. Spearman rank correlations among immunophenotypic profiles were analyzed. Recursive partitioning classified subjects as patients or normal controls based on CD8(+)CCR7(+) T-cell percentages. Kaplan-Meier plots estimated disease-free survival (DFS). RESULTS: The CD8(+)CCR7(+) T-cell frequency was low, whereas that of total CD8(+)CCR7(neg) and ANXV-binding CD8(+)CCR7(neg) T cells was higher in patients with HNSCC than in normal controls (P < 0.001-0.0001). ANXV binding correlated with the absence of CCR7 on CD8(+) T cells (P < 0.001). ANXV binding was negatively correlated with the CD8(+)CD45RO(neg)CCR7(+) (T(N)) cell frequency (P < 0.01) but positively correlated (P < 0.01) with that of CD8(+)CD45RO(+)CCR7(+) (T(CM)) T cells and of the two CCR7(neg) subsets (T(PM) and T(TD)). In recursive partitioning models, the CD8(+)CCR7(+) T-cell frequency of 31% distinguished patients from normal controls with 77% to 88% accuracy after cross-validation. In 25 patients tested before any therapy, the CD8(+)CCR7(+) T-cell frequency of less than 28% predicted disease recurrence within 4 years of definitive therapy (P < 0.0115). CONCLUSION: The CD8(+)CCR7(+) T-cell frequency in HNSCC patients' blood tested at diagnosis can discriminate them from normal controls and predicts disease recurrence.

[Immune elements of pathogenesis of multiorgan failure syndrome in newborns].

Expression of clusters determination of T-cells immune links (CD4, CD8, CD95) and level of interferon-alpha at newborns with multiorgan failure syndrome were investigated. It were shown supressive character of immune reactions and reduction the level of interferon-alpha in this contingent of patients.

Impact of fish oil enriched total parenteral nutrition on elderly patients after colorectal cancer surgery.

BACKGROUND: Polyunsaturated omega-3 fatty acids may beneficially influence healing processes and patient outcomes. The aim of this research was to study the clinical efficacy of fish oil enriched total parenteral nutrition in elderly patients after colorectal cancer surgery. METHODS: Fifty-seven elderly patients with colorectal cancer were enrolled in this prospective, randomized, double-blind, controlled clinical trial. All patients received isocaloric and isonitrogenous total parenteral nutrition by continuous infusion (20 - 24 hours per day) for seven days after surgery. The control group (n = 28) received 1.2 g/kg soybean oil per day, whereas the treatment group (n = 29) received 0.2 g/kg fish oil and 1.0 g/kg soybean oil per day. Blood samples were taken pre-operatively, and at days one and eight after the operation. The plasma levels of CD4, CD8, CD4/CD8, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were measured. Clinical outcomes were then analysed. RESULTS: Patient characteristics were comparable between the two groups. At day eight post-surgery, IL-6, TNF-α and CD8 titres were lower in the treatment group when compared to the control group; these results reached statistical significance. In the treatment group, there were fewer infectious complications and incidences of systemic inflammatory response syndrome (SIRS), and shorter lengths of hospital stay were observed. The total cost of medical care was comparable for the two groups. No serious adverse events occurred in either group. CONCLUSIONS: Fish oil 0.2 g/kg per day administrated to elderly patients after colorectal surgery was safe and may shorten the length of hospital stay and improve clinical outcomes.