18 research outputs found

    Circulating immunophenotypes are potentially prognostic in follicular cell-derived thyroid cancer

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    BackgroundExploring the immune interface of follicular cell-derived thyroid cancer has prognostic and therapeutic potential. The available literature is lacking for comprehensive immunophenotyping in relation to clinical outcomes. In this study, we identify circulating immunophenotypes associated with thyroid cancer prognosis.MethodsWe conducted a pilot observational study of adults with follicular cell-derived thyroid cancer who underwent surgery at our tertiary care referral center and had consented for flow cytometry on peripheral blood collected at the time of thyroidectomy.ResultsOf the 32 included subjects, 20 (62%) had well differentiated, 5 (16%) had poorly differentiated, and 7 (22%) had anaplastic thyroid cancer. The most frequent AJCC stage was 4 (59%) and the ATA risk of recurrence category was high (56%). Patients with AJCC stage 3/4 demonstrated fewer circulating mononuclear cells (CD45+), more monocytes (CD14+), fewer total lymphocytes (CD14-), fewer T cells (CD3+), fewer CD4+ T cells, fewer gamma-delta T cells, fewer natural killer (NK) T-like cells, more myeloid-derived suppressor cells (MDSCs; Lin-CD33+HLADR-), and more effector memory T cells but similar CD8+ T cells compared to stage1/2. Immunophenotype comparisons by ATA risk stratification and course of thyroid cancer were comparable to those observed for stage, except for significant differences in memory T cell subtypes. The median follow-up was 58 months.ConclusionsAggressive follicular cell-derived thyroid cancer either at presentation or during follow-up is associated with down-regulation of the T cell populations specifically CD4+ T cells, gamma-delta T cells, and NK T-like cells but up-regulation of MDSCs and altered memory T cells. These immunophenotypes are potential prognostic biomarkers supporting future investigation for developing targeted immunotherapies against advanced thyroid cancer

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Journey Through the Federal Loophole; Behavioral Trends Among Physicians Practicing Regenerative Medicine

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    Regenerative medicine therapies have shown potential in treating conditions previously deemed incurable. Though still categorized as investigational by the Food and Drug Administration (FDA), these treatments have gained popularity and are offered at both public and private practices. Platelet Rich Plasma (PRP) and Bone Marrow Aspirate Concentrate (BMAC) regenerative medicine therapies are provided to patients at the Mayo Clinic at multiple departments throughout the institution at different locations. This study characterized the practice, preferences of the practitioners, and perceptions of product efficacy, safety and regulations. Data was collected using a questionnaire focusing on attitudes and behaviors of those performing BMAC and PRP procedures. A total of 8 Mayo Clinic practitioners responded to the questionnaire. The cumulative outcomes of the study provided a baseline understanding of the procedures, how often they are performed, and the indications for which they are most commonly used. Detriments to performing research were also studied and most commonly identified as lack of time and funding. Perceptions of current regulations, reactions to scenarios of possible outcomes of controlled double blind clinical trials and their impact on the practice were also assessed. Results were also used to identify how to best implement new FDA regulations into the practice

    A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood

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    Abstract Background Exercise immunology has become a growing field in the past 20 years, with an emphasis on understanding how different forms of exercise affect immune function. Mechanistic studies are beginning to shed light on how exercise may impair the development of cancer or be used to augment cancer treatment. The beneficial effects of exercise on the immune system may be exploited to improve patient responses to cancer immunotherapy. Methods We investigated the effects of acute exercise on the composition of peripheral blood leukocytes over time in a male population of varying fitness. Subjects performed a brief maximal intensity cycling regimen and a longer less intense cycling regimen at separate visits. Leukocytes were measured by multi-parameter flow cytometry of more than 50 immunophenotypes for each collection sample. Results We found a differential induction of leukocytosis dependent on exercise intensity and duration. Cytotoxic natural killer cells demonstrated the greatest increase (average of 5.6 fold) immediately post-maximal exercise whereas CD15+ granulocytes demonstrated the largest increase at 3 h post-maximal exercise (1.6 fold). The longer, less intense endurance exercise resulted in an attenuated leukocytosis. Induction of leukocytosis did not differ in our limited study of active (n = 10) and sedentary (n = 5) subjects to exercise although we found that in baseline samples, sedentary individuals had elevated percentages of CD45RO+ memory CD4+ T cells and elevated proportions of CD4+ T cells expressing the negative immune regulator programmed death-1 (PD-1). Finally, we identified several leukocytes whose presence correlated with obesity related fitness parameters. Conclusions Our data suggests that leukocytes subsets are differentially mobilized into the peripheral blood and dependent on the intensity and duration of exercise. Pre-existing compositional differences of leukocytes were associated with various fitness parameters

    Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis.

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    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a median lifespan of 2-3 years after diagnosis. There are few meaningful treatments that alter progression in this disease. Preclinical and clinical studies have demonstrated that neuroinflammation may play a key role in the progression rate of ALS. Despite this, there are no validated biomarkers of neuroinflammation for use in clinical practice or clinical trials. Biomarkers of neuroinflammation could improve patient management, provide new therapeutic targets, and possibly help stratify clinical trial selection and monitoring. However, attempts to identify a singular cause of neuroinflammation have not been successful. Here, we performed multi-parameter flow cytometry to comprehensively assess 116 leukocyte populations and phenotypes from lymphocytes, monocytes, and granulocytes in a cohort of 80 ALS patients. We identified 32 leukocyte phenotypes that were altered in ALS patients compared to age and gender matched healthy volunteers (HV) that included phenotypes of both inflammation and immune suppression. Unsupervised hierarchical clustering and principle component analysis of ALS and HV immunophenotypes revealed two distinct immune profiles of ALS patients. ALS patients were clustered into a profile distinct from HVs primarily due to differences in a multiple T cell phenotypes, CD3+CD56+ T cells and HLA-DR on monocytes. Patients clustered into an abnormal immune profile were younger, more likely to have a familial form of the disease, and survived longer than those patients who clustered similarly with healthy volunteers (344 weeks versus 184 weeks; p = 0.012). The data set generated from this study establishes an extensive accounting of immunophenotypic changes readily suitable for biomarker validation studies. The extensive immune system changes measured in this study indicate that normal immune homeostatic mechanisms are disrupted in ALS patients, and that multiple immune states likely exist within a population of patients with ALS

    Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer

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    Stereotactic body radiation therapy (SBRT) can positively influence an antitumor immune response by inducing necrotic cell death. SBRT also been shown to eliminate tumors outside the radiation therapy field through an immune-mediated process known as the abscopal effect. Recent advances in immunotherapy may provide new therapeutic approaches for patients with liver cancer. Therefore, understanding the immune status of patients with cancer will likely guide how immunotherapy might be used in combination with SBRT. We hypothesized that we would observe changes in circulating blood immune cell populations of patients who received SBRT for liver tumors. Therefore, we assessed 110 immunophenotypes in the peripheral blood of 10 patients with liver cancer or metastases to the liver pretreatment and 2 posttreatment time points. Patients with liver cancer and metastatic patients both exhibited several immunophenotypic abnormalities at baseline compared with a group of healthy volunteer controls. In longitudinal studies, SBRT caused a specific reduction in CD3+ T cell counts and immature CD56brCD16− NK cell counts. The immune profiling and potential identification of circulating biomarkers shown here could lead to the design of combinatorial approaches with SBRT and immunotherapy to optimize the timing of treatment and direct the most effective immunotherapy with SBRT

    Different immunophenotypic biomarkers associate with clinical parameters in the two ALS immune profiles.

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    <p>Immune phenotypes were plotted against ALSFRS-R score or slope (ALSFRS-R points/month). XY graphs of correlations show p-value and Spearman r value. Lines represent the best fit resulting from linear regression analysis. Closed circles represent healthy volunteers, open squares represent ALS patients in Profile 1, and open diamonds represent ALS patients in Profile 2. <b>A.</b> Correlations of selected immunophenotypes to ALSFRS-R score in Profile 1 patients (top row) versus Profile 2 (bottom row). <b>B.</b> Correlations of selected immunophenotypes to slope in ALS Profile 1 patients. <b>C.</b> Survival curves of patients in each profile sub-grouped by cut-off values for PD-1<sup>+</sup> CD4<sup>+</sup> T cells. 19.7% was the cut-off value representing the median value for Profile 1 patients (Hi PD-1≥ 19.7; Lo PD-1< 19.7) and 19.5% was the cut-off value for Profile 2 patients. For CD3<sup>+</sup>CD56<sup>+</sup> T cells, 104.62 cells/μl was used as a cut-off value for Profile 2 patients and 28.21 cells/μl was used for Profile 1. <b>D.</b> CD4<sup>+</sup>CD45RA<sup>+</sup> naïve T cells show dissimilar age related associations between Profile 2 ALS patients, Profile 1 ALS patients, and healthy volunteers.</p

    Additional phenotypic characterizations of CD3<sup>+</sup>CD56<sup>+</sup> T cells.

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    <p><b>A.</b> CD3<sup>+</sup>CD56<sup>+</sup> T cell counts plotted against age (years) for sub-grouped ALS patients and healthy volunteers. <b>B.</b> Correlation between CD8<sup>+</sup> T cell counts and CD3<sup>+</sup>CD56<sup>+</sup> T cell counts (left) and the CD4:CD8 ratios are lower in CD56<sup>+</sup> than CD56<sup>-</sup> T cells. <b>C.</b> Comparison of the percentage of CD28 negative cells in CD56<sup>-</sup> (filled shapes) and CD56<sup>+</sup> cells (open shapes) for both CD8 (circles) and CD4 (squares) subsets. <b>D.</b> Examples of CD28/CD56 dot plots gated from CD4 and CD8 subsets from two ALS patients.</p
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