Effects of pre-transport diet, transport duration and transport condition on immune cell subsets, haptoglobin, cortisol and bilirubin in young veal calves

The aim of this study was to investigate effects of pre-transport diets, transport durations and transport conditions on immune cell subsets, haptoglobin, cortisol and bilirubin of young calves upon arrival at the veal farm. An experiment was conducted with a 2 × 2 × 2 factorial arrangement with 3 factors: 1) provision of rearing milk or electrolytes at the collection center (CC); 2) transport duration (6 or 18 hours) and 3) transport condition (open truck or conditioned truck). Holstein-Friesian and cross-bred calves were used (N = 368; 18 ± 4 days; 45.3 ± 3.3 kg). Blood samples were collected from calves (N = 128) at the collection center, immediately post-transport (T0) and 4, 24, 48 hours, week 1, 3 and 5 post-transport. Blood was analyzed for cortisol, bilirubin, haptoglobin, IgG and IgM. Moreover, cell counts of neutrophils, lymphocytes, monocytes, basophils and eosinophils were measured in blood samples taken at the collection center and T0. In these same blood samples, different lymphocyte populations were characterized by flow cytometry, including CD14+ cells, NK cells, δγ+ T cells, CD8+ cells, CD4+ cells and CD21+ cells. Calves transported in the conditioned truck had higher amounts of white blood cell count (WBC) (Δ = 1.39 × 109/l; P = 0.01), monocytes (Δ = 0.21 × 109/l; P = 0.04), neutrophils (Δ = 0.93 × 109/l; P = 0.003), than calves transported in the open truck regardless, of pre-transport diet or transport duration. The study showed that transport condition and duration influenced parts of the innate immune system of young veal calves. Cortisol, bilirubin and WBC seemed to be connected by similar underlying mechanisms in relation to transport conditions. However, it is unclear which specific pathways in the immune system of young calves are affected by different transport conditions (e.g. temperature, humidity, draught).

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Korean Red Ginseng Plays an Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets

Molecules ◽

10.3390/molecules25071492 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1492 ◽

Cited By ~ 1

Author(s):

Kun Kuk Shin ◽

Young-Su Yi ◽

Jin Kyeong Kim ◽

Haeyeop Kim ◽

Mohammad Amjad Hossain ◽

...

Keyword(s):

Mrna Expression ◽

Immune Cell ◽

Serum Levels ◽

Red Ginseng ◽

Aging Effects ◽

Thymic Involution ◽

Korean Red Ginseng ◽

Immune Cell Subsets ◽

Underlying Mechanisms ◽

Old Mice

Despite previous reports of anti-aging effects of Korean red ginseng (KRG), the underlying mechanisms remain poorly understood. Therefore, this study investigated possible mechanisms of KRG-mediated anti-aging effects in aged mice. KRG significantly inhibited thymic involution in old mice. Interestingly, KRG only increased protein expression, but not mRNA expression, of aging-related genes Lin28a, GDF-11, Sirt1, IL-2, and IL-17 in the thymocytes of old mice. KRG also modulated the population of some types of immune cells in old mice. KRG increased the population of regulatory T cells and interferon-gamma (IFN-γ)-expressing natural killer (NK) cells in the spleen of old mice, but serum levels of regulatory T cell-specific cytokines IL-10 and TGF-β were unaffected. Finally, KRG recovered mRNA expression of Lin28a, GDF-11, and Sirt1 artificially decreased by concanavalin A (Con A) in both thymocytes and splenocytes of old mice without cytotoxicity. These results suggest that KRG exerts anti-aging effects by preventing thymic involution, as well as modulating the expression of aging-related genes and immune cell subsets.

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Characterization of Immune Cell Subsets of Tumor Infiltrating Lymphocytes in Brain Metastases

Biology ◽

10.3390/biology10050425 ◽

2021 ◽

Vol 10 (5) ◽

pp. 425

Author(s):

Priyakshi Kalita-de Croft ◽

Haarika Chittoory ◽

Tam H. Nguyen ◽

Jodi M. Saunus ◽

Woo Gyeong Kim ◽

...

Keyword(s):

Brain Metastasis ◽

Immune Cell ◽

Immune Surveillance ◽

Tumor Infiltrating Lymphocytes ◽

Cd8 Cells ◽

Targeted Analysis ◽

Immune Cell Subsets ◽

Checkpoint Molecule ◽

Formalin Fixed Paraffin Embedded ◽

Infiltrating Lymphocytes

The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per sample. Classifying tumors as either high (>30%) or low (<30%) TILs, we found that increased TILs density correlated with survival. Phenotyping these TILs we found tumors with low TILs had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p < 0.01) as well as in their microenvironment (p < 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p < 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p < 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

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Several Immune Cell Subsets Are Associated with Outcome in the Microenvironment of Follicular Lymphoma.

Blood ◽

10.1182/blood.v114.22.3953.3953 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3953-3953

Author(s):

Björn Engelbrekt Wahlin ◽

Mohit Aggarwal ◽

Santiago Montes-Moreno ◽

Luis Francisco Gonzalez ◽

Giovanna Roncador ◽

...

Keyword(s):

Multivariate Analysis ◽

Follicular Lymphoma ◽

B Cell ◽

Immune Cell ◽

Univariate Analysis ◽

Cd4 Cells ◽

Cell Stimulation ◽

Cd8 Cells ◽

Good Outcome ◽

Immune Cell Subsets

Abstract Abstract 3953 Poster Board III-889 AIMS Several studies concur that the microenvironment determines outcome in follicular lymphoma (FL), but they disagree regarding which components thereof are important. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors. Specifically, we hypothesized that (1) CD8+ cells are associated with good prognosis (presumably due to tumor cell killing), as are (2) cells positive for programmed death-1 (PD-1) or FOXP3 (due to diminished B-cell stimulation), while (3) CD4+ cells are associated with poor prognosis (due to B-cell stimulation). PATIENTS AND METHODS Seventy FL patients with extreme clinical outcome (“poor” and “good” cases) were identified in a cohort of 197 patients. The criterion for poor outcome was death from lymphoma <5 years after diagnosis (n=33). The general criteria for good outcome were absence of a lymphoma-related death and/or transplantation and one of the following three statements had to be true: (1) never treated against lymphoma and followed for ≥5 years (n=11); (2) never relapsed after first-line anti-lymphoma treatment and followed for ≥8 years (n=14); (3) relapsed but never received intensive or frequent (≥3 years between) treatments and followed for ≥10 years (n=12), rendering totally 37 good-outcome patients. A tissue microarray was constructed from diagnostic and relapse biopsies of these 70 patients. Sections of the microarray were stained for CD3, CD7, CD4, FOXP3, PD-1, CD8, TIA-1, granzyme B, perforin, CD57, CD56, CD68, and tryptase. The number of positive cells for each staining were quantified using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). RESULTS Between the two clinical extreme groups there were great differences in the FL International Prognostic Index (FLIPI), as expected (P<0.0001). In univariate analysis, the amounts of several immune subsets were different between the two groups with borderline or stronger significance. These subsets were taken to multivariate analysis together with the FLIPI. Independently of the FLIPI, CD4+ cells were associated with poor (Odds Ratio [OR] 1.26; P=0.025) but PD-1+ (OR 0.58; P=0.020) and CD8+ (OR 0.94; P=0.024) cells with good outcome. In a second multivariate analysis, where the subsets in the follicular and interfollicular comparments were analyzed (again in competition with the FLIPI), the prognostic values of CD4+ and PD-1+ cells were accentuated when they were follicular (OR 2.16; P=0.010 and OR 0.34; P=0.019, respectively), and that of CD8+ cells when interfollicular (OR 0.86; P=0.014). Follicular FOXP3+ cells were also associated with good outcome (OR 0.09; P=0.018) and interfollicular CD68+ cells with poor (OR 1.36; P=0.040). CONCLUSION We conclude that there are many important immune cell subsets in the microenvironment of FL. Independently of the FLIPI, and of each other, PD-1+, FOXP3+, CD4+, CD8+, and CD68+ cells correlate with outcome. This suggests several different but not mutually exclusive mechanisms which all affect the course of the disease. Disclosures: No relevant conflicts of interest to declare.

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Relevance of QuantiFERON-TB Gold Plus and Heparin-Binding Hemagglutinin Interferon-γ Release Assays for Monitoring of Pulmonary Tuberculosis Clearance: A Multicentered Study

Frontiers in Immunology ◽

10.3389/fimmu.2020.616450 ◽

2021 ◽

Vol 11 ◽

Author(s):

Carole Chedid ◽

Eka Kokhreidze ◽

Nestani Tukvadze ◽

Sayera Banu ◽

Mohammad Khaja Mafij Uddin ◽

...

Keyword(s):

Immune Cell ◽

Interferon Γ ◽

Sputum Culture ◽

Heparin Binding ◽

Monitoring Methods ◽

Blood Samples ◽

Sputum Culture Conversion ◽

Cell Counts ◽

Release Assay ◽

Culture Conversion

BackgroundTuberculosis (TB) is a leading infectious cause of death. To improve treatment efficacy, quicker monitoring methods are needed. The objective of this study was to monitor the response to a heparin-binding hemagglutinin (HBHA) interferon-γ (IFN-γ) release assay (IGRA) and QuantiFERON-TB Gold Plus (QFT-P) and to analyze plasma IFN-γ levels according to sputum culture conversion and immune cell counts during treatment.MethodsThis multicentered cohort study was based in Bangladesh, Georgia, Lebanon, Madagascar, and Paraguay. Adult, non-immunocompromised patients with culture-confirmed pulmonary TB were included. Patients were followed up at baseline (T0), after two months of treatment (T1), and at the end of therapy (T2). Clinical data and blood samples were collected at each timepoint. Whole blood samples were stimulated with QFT-P antigens or recombinant methylated Mycobacterium tuberculosis HBHA (produced in Mycobacterium smegmatis; rmsHBHA). Plasma IFN-γ levels were then assessed by ELISA.FindingsBetween December 2017 and September 2020, 132 participants completed treatment, including 28 (21.2%) drug-resistant patients. rmsHBHA IFN-γ increased significantly throughout treatment (0.086 IU/ml at T0 vs. 1.03 IU/ml at T2, p < 0.001) while QFT-P IFN-γ remained constant (TB1: 0.53 IU/ml at T0 vs. 0.63 IU/ml at T2, p = 0.13). Patients with low lymphocyte percentages (<14%) or high neutrophil percentages (>79%) at baseline had significantly lower IFN-γ responses to QFT-P and rmsHBHA at T0 and T1. In a small group of slow converters (patients with positive cultures at T1; n = 16), we observed a consistent clinical pattern at baseline (high neutrophil percentages, low lymphocyte percentages and BMI, low TB1, TB2, and MIT IFN-γ responses) and low rmsHBHA IFN-γ at T1 and T2. However, the accuracy of the QFT-P and rmsHBHA IGRAs compared to culture throughout treatment was low (40 and 65% respectively). Combining both tests improved their sensitivity and accuracy (70–80%) but not their specificity (<30%).ConclusionWe showed that QFT-P and rmsHBHA IFN-γ responses were associated with rates of sputum culture conversion. Our results support a growing body of evidence suggesting that rmsHBHA IFN-γ discriminates between the different stages of TB, from active disease to controlled infection. However, further work is needed to confirm the specificity of QFT-P and rmsHBHA IGRAs for treatment monitoring.

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Kinetics of Immune Reconstitution in Event-Free Patients: Establishing Reference Values for Immune Recovery of Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.5772.5772 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5772-5772

Author(s):

Xu-Ying Pei ◽

Yu Wang ◽

Lan-Ping Xu ◽

Xiao-Hui Zhang ◽

Xiang-Yu Zhao ◽

...

Keyword(s):

Reference Values ◽

Immune Reconstitution ◽

Immune Cell ◽

First Year ◽

Immune Recovery ◽

Hematopoietic Stem ◽

Post Transplant ◽

Cell Counts ◽

Healthy Donors ◽

Immune Cell Subsets

Abstract Background: Immune reconstitution (IR) is strongly associated with clinical outcomes after hematopoietic stem cell transplantation (HSCT). So far, there are no optimal reference values for recovered immune cell subsets after HSCT, and approaches to enhance post-transplant IR based on data from health donors have their limitations. Therefore, reference values need to be established for immune cell counts to monitor IR and identify high-risk patients needing aggressively supportive treatment. Methods: Between January 2011 and December 2013, 706 consecutive patients who received HLA-matched sibling transplantation (MSDT) or haploidentical transplantation (haplo-SCT) modality participated in this study. Finally a total of 144 patients who did not experience transplant complications such as poor graft function, grades II-IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, relapse or death in the first year after transplant were available for immune cell subset testing between day 30 and 365, and were analyzed in this study. To provide reference values that could be used for all recipients, the effects of recipient age, gender, and underlying disease on IR were investigated. In addition, 41 healthy donors underwent single time-point immune analysis, and the data were used as a normal control. Results: The 4-year probability of relapse, non-relapse mortality, leukemia-free survival, and overall survival was 5% (95% CI: 1%-9%), 1% (95% CI: 0%-2%), 95% (95% CI: 90%-99%), and 98% (95% CI: 96%-100%), respectively. Monocytes recovered rapidly and persisted at higher levels than normal during the first year after transplantation. The total CD3+ T cell counts were very low in the first 30 days but normalized by 90 days post-transplant. CD4+ helper T cells recovered very slowly and did not reach normal range by 1 year after transplantation. The absolute numbers of CD8+ T cells were higher after 90 days post-transplant compared to healthy donors. The recovery of CD19+ B cells was delayed during 1 year after transplantation. All immune cell subsets except monocytes recovered faster after MDST than haplo-SCT. By univariate and multivariate analysis, the haplo-SCT modality was confirmed to be associated with immune recovery. So the reference values for recovered immune cell subgroups were provided for MSDT and haplo-SCT, respectively. Conclusion: Our results suggest that patients with IR comparable to the reference values could have superior survival and the immune cells may not have to recover to healthy donor levels in the first year after transplantation. We emphasize that data from this recipient cohort should be understood as reference values for immune cell counts post-transplant for patients receiving HSCT. Acknowledgments: This work was supported, in part, by the National High Technology Research and Development Program of China (Program 863; Grant No. 2013AA020401) and the National Natural Science Foundation of China (Grant No. 81470342). We thank the faculty members who collected samples and analyzed the flow cytometry data. Disclosures No relevant conflicts of interest to declare.

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Hematopoietic Stem Cell Transplantation (HSCT) with Omidubicel Is Associated with Robust Immune Reconstitution and Lower Rates of Severe Infection Compared to Standard Umbilical Cord Blood Transplantation

Blood ◽

10.1182/blood-2021-153408 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 333-333

Author(s):

Paul Szabolcs ◽

Stuart Levy ◽

Dima Yackoubov ◽

Aviad Pato ◽

Einat Galamidi-Cohen ◽

...

Keyword(s):

B Cell ◽

Viral Infections ◽

Immune Cell ◽

Nk Cell ◽

Hematopoietic Stem ◽

Post Transplant ◽

Cell Counts ◽

Immune Cell Subsets ◽

Cell Current ◽

One Year

Abstract Introduction Omidubicel is an advanced cell therapy for allogeneic hematopoietic stem cell transplantation (HSCT), derived from appropriately HLA-matched umbilical cord blood (UCB) and comprised of ex-vivo expanded CD133+ cells and a non-cultured lymphocyte-containing fraction. Recent results of a global phase III trial of omidubicel vs standard UCB showed more rapid hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients (pts) randomized to omidubicel (Horwitz et al, Blood, 2021). We now report results of correlative immune reconstitution (IR) studies in this trial (NCT02730299). Methods A total of 125 pts aged 13-65 with hematologic malignancies were randomized to allogeneic transplantation with omidubicel or standard UCB following myeloablative conditioning; 108 pts were transplanted per protocol. An optional IR sub-study was conducted and blood was collected at intervals from Day 7 through one year post-transplant. Cryopreserved samples were analyzed in a central laboratory (Covance) using 16-color and 14-color panels and flow cytometric assays to explore T cell, NK cell, B cell, monocyte, and dendritic cell (DC) subsets. Means, medians, ranges, and standard errors were used to summarize cell counts, and one-tailed t-tests were used to compare counts in the two treatment arms. Results A total of 37 pts from 15 sites consented to the IR sub-study, representing 34% of the per protocol population; 17 pts were transplanted with omidubicel and 20 pts with control (15 [75%] of control with double UCB). Median age was 30 (range: 13-62) years for omidubicel pts and 43 (range: 19-55) years for controls in the sub-study. Median CD3+ content of omidubicel prior to cryopreservation was lower (180 x 10^6; range: 71-580 cells) than that of controls post-thaw (516 x 10^6, range: 183-990 cells). Omidubicel pts achieved neutrophil engraftment at a median of 10 (range: 6-28) days post-transplant compared to a median of 18.5 (range: 14-40) days in controls. Omidubicel pts had fewer BMT-CTN Grade 3 viral infections in the first-year post-transplant than controls (6% vs. 25%, respectively). At Day 7 post-transplant, CD4+ T cell counts were significantly higher in omidubicel pts (37x10^3 cells/ml) than in controls (17x10^3 cells/ml, p=0.011). B cells (12x10^3 vs 1x10^3 cells/ml, p=0.013) and NK cells (6x10^3 vs 3 x10^3 cells/ml, p=0.016), as well as monocyte and DC subsets, were also significantly higher in omidubicel pts (Table). Day 14 results similarly demonstrated higher counts of circulating immune cell subsets in omidubicel pts than in controls (Table). Higher B cell counts were observed in omidubicel pts than in controls at 6 months ([863±463] x10^3 vs. [543±221] x10^3 cells/ml, p=0.03) and one year ([1492±370] x10^3 vs [763±150] x10^3, p=0.02) following transplant (Figure). Conclusions Circulating immune cell subsets were consistently higher in omidubicel pts than controls as early as one week after transplant, and higher B cell counts persisted through one year. These findings correlated with the clinical observation of fewer severe bacterial, fungal, and viral infections in pts treated with omidubicel compared to standard UCB. These results demonstrate that rapid hematopoietic recovery in pts transplanted with omidubicel is accompanied by the early and robust appearance of a broad array of lymphocyte, monocyte, DC, and NK cell subsets, despite substantially fewer numbers of these cells infused, suggesting a facilitator effect of omidubicel on their in vivo expansion. Figure 1 Figure 1. Disclosures Szabolcs: Gamida Cell: Consultancy; Prevail Therapeutics: Consultancy; Sotiria/Forge Biologics: Current equity holder in publicly-traded company. Levy: Gamida Cell: Current Employment. Yackoubov: Gamida Cell: Current Employment. Pato: Gamida Cell: Current Employment. Galamidi-Cohen: Gamida Cell, Ltd: Current Employment. Horwitz: Gamida Cell: Research Funding.

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Effect of Pleuran (β-glucan from Pleurotus ostreatus) supplementation on cellular immune response after intensive exercise in elite athletes

Applied Physiology Nutrition and Metabolism ◽

10.1139/h10-070 ◽

2010 ◽

Vol 35 (6) ◽

pp. 755-762 ◽

Cited By ~ 35

Author(s):

Marián Bobovčák ◽

Renata Kuniaková ◽

Ján Gabriž ◽

Juraj Majtán

Keyword(s):

Immune System ◽

Pleurotus Ostreatus ◽

Immune Cell ◽

Nk Cell ◽

Elite Athletes ◽

Recovery Period ◽

Cell Activity ◽

Positive Effects ◽

Cell Counts ◽

Intensive Exercise

Excessive and exhausting physical loads depress the immune system. Carbohydrate consumption may minimize the postexercise suppression of the innate immune system. β-Glucan is a well-known immunomodulator, with positive effects on the functioning of immunocompetent cells. The goal of this study was to determine whether β-glucan dietary supplementation from the mushroom Pleurotus ostreatus decreases the suppressed immune system responses induced by short-term high-intensity exercise in humans. In this double-blind pilot study, 20 elite athletes were randomized to β-glucan (n = 9) or placebo (n = 11) groups; these groups consumed 100 mg of β-glucan (Imunoglukan) or placebo supplements, respectively, once a day for 2 months. Venous whole blood was collected before and after 2 months of supplementation (baseline), both immediately and 1 h after (recovery period) a 20-min intensive exercise bout at the end of the supplementation period. The blood samples were used to measure the cell counts of leukocytes, erythrocyte, and lymphocytes; subpopulations of lymphocytes, granulocytes, and monocytes; and natural killer (NK) cell activity (NKCA). A 28% reduction in NKCA (p < 0.01) below the baseline value was observed in the placebo group during the recovery period, whereas no significant reduction in NKCA was found in the β-glucan group. In addition, no significant decrease in NK cell count was measured in the β-glucan group during the recovery period. Immune cell counts did not differ significantly between the groups. These results indicate that insoluble β-glucan supplementation from P. ostreatus may play a role in modulating exercise-induced changes in NKCA in intensively training athletes.

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Breast-fed and bottle-fed infant rhesus macaques develop distinct gut microbiotas and immune systems

Science Translational Medicine ◽

10.1126/scitranslmed.3008791 ◽

2014 ◽

Vol 6 (252) ◽

pp. 252ra120-252ra120 ◽

Cited By ~ 74

Author(s):

Amir Ardeshir ◽

Nicole R. Narayan ◽

Gema Méndez-Lagares ◽

Ding Lu ◽

Marcus Rauch ◽

...

Keyword(s):

Immune System ◽

Immune Cell ◽

Rhesus Macaques ◽

Microbial Colonization ◽

T Helper 17 ◽

Immune Systems ◽

Memory Pool ◽

Immune Cell Subsets ◽

Breast Fed ◽

Infant Rhesus

Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be. We show that breast-fed and bottle-fed infant rhesus macaques develop markedly different immune systems, which remain different 6 months after weaning when the animals begin receiving identical diets. In particular, breast-fed infants develop robust populations of memory T cells as well as T helper 17 (TH17) cells within the memory pool, whereas bottle-fed infants do not. These findings may partly explain the variation in human susceptibility to conditions with an immune basis, as well as the variable protection against certain infectious diseases.

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A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma

BMC Cancer ◽

10.1186/s12885-021-08636-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Monique C. Tavares ◽

Cristina D. Sampaio ◽

Geraldine E. Lima ◽

Victor P. Andrade ◽

Daniel G. Gonçalves ◽

...

Keyword(s):

Breast Cancer ◽

Immune System ◽

Tumor Cells ◽

Triple Negative ◽

Immune Cell ◽

Breast Cancer Subtype ◽

Tumor Stroma ◽

Prognostic Impact ◽

Cell Counts ◽

Dismal Prognosis

Abstract Background Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. Methods Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. Results We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. Conclusion TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.

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PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21165918 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5918

Author(s):

Ana Bocanegra ◽

Ester Blanco ◽

Gonzalo Fernandez-Hinojal ◽

Hugo Arasanz ◽

Luisa Chocarro ◽

...

Keyword(s):

Overall Survival ◽

Monoclonal Antibodies ◽

Immune System ◽

Immune Cell ◽

Treatment Strategies ◽

Progression Free Survival ◽

Free Survival ◽

Immune Cell Subsets ◽

Anticancer Treatment ◽

Tumor Biopsies

The use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of the treatment is PD-L1 expression in tumor biopsies. Nevertheless, even when having PD-L1-positive tumors, numerous patients do not respond to these treatments. Considering the high cost of these therapies and the risk of immune-related adverse events during therapy, it is necessary to identify additional biomarkers that would facilitate stratifying patients in potential responders and non-responders before the start of immunotherapies. Here, we review the utility of PD-L1 expression not only in tumor cells but in immune system cells and their influence on the antitumor activity of immune cell subsets.

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