Serial changes in PD1/PDL1 expression in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint blockade (CPB).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 109-109
Author(s):  
Alice Tzeng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Jin Sub Kim ◽  
Paul G Pavicic ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Immune Marker ◽  
Marker Expression ◽  
Median Change

109 Background: Since CPB may alter immune marker expression in key immunomodulatory populations such as myeloid-derived suppressor cells (MDSC) and CD8+ cytotoxic T lymphocytes (CTL), we evaluated PD1/PDL1 expression in longitudinal samples from mUC pts treated with CPB. Methods: Serial peripheral blood samples were collected from mUC pts who received CPB. PD1/PDL1 and VISTA expression was measured in MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from live peripheral blood mononuclear cells using flow cytometry. MDSC subsets were further defined as (G)ranulocytic (CD15+CD14−), (M)onocytic (CD15−CD14+), and (I)mmature (CD15−CD14−). PD1/PDL1 and VISTA expression was presented as % of each MDSC subset or CTL. Wilcoxon signed-rank tests and mixed-model regression analyses were performed to assess changes in immune marker expression after CPB. Results: Of 30 CPB-treated pts with ≥ 2 blood samples for analysis, 21 received anti-PDL1 (20 atezolizumab/1 avelumab; [A]) and 9 received anti-PD1 (pembrolizumab [P]). Median age at diagnosis was 69.5 (46–81), 77% men, 33% never smokers, 63% pure UC, 70% bladder primary, 20% prior intravesical BCG, 37% prior neoadjuvant chemotherapy, 63% prior cystectomy. Best overall responses to CPB were 3 PR/13 SD/5 PD (A) and 1 CR/1 PR/4 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC, while those of P correlated with decreased %PD1+ M- and I- MDSC (Table). No significant changes in VISTA expression were detected. In 11 A-treated pts with samples before/after the 1st dose, %PDL1+ M- and I- MDSC decreased (median change −25.5 and −5.7; p = 0.02 and 0.03) and %PD1+ CTL increased (median change +2.4; p = 0.02) between 1st and 2nd samples. Conclusions: In this mUC pt cohort, distinct post-tx changes in %PD1/PDL1 in MDSC subsets and CTL occurred based on CPB (anti-PD1 vs anti-PDL1). Further analysis of correlations between CPB, immune marker expression, clinicopathologic factors, and outcomes is ongoing in a larger cohort. Mean absolute change in marker expression per dose in pts treated with CPB. [Table: see text]

Immunological correlates of response to immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 454-454
Author(s):  
Alice Tzeng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Jin Sub Kim ◽  
Paul G Pavicic ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Never Smokers

454 Background: Identification of biomarkers predictive of response to ICI could help guide treatment (tx) decisions. We assessed the correlation between PD1/PDL1 expression in key immunomodulatory subsets (myeloid-derived suppressor cells [MDSC]; CD8+ T cells) and tx response in mUC pts treated with ICI. Methods: Serial peripheral blood samples were collected from mUC pts treated with ICI. Flow cytometry was used to quantify PD1/PDL1 expression in MDSC (CD33+HLADR−) and CD8+ T cells (CD8+CD4−) from live peripheral blood mononuclear cells. MDSC were subdivided into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14− CD15+), and immature (I)-MDSC (CD14− CD15−). Mixed-model regression and Wilcoxon rank-sum tests were performed to assess post-ICI changes in immune marker expression and identify correlations between PD1/PDL1 expression and best overall response (BOR) to ICI. Results: Of 36 ICI-treated pts with ≥2 blood samples, 24 received anti-PDL1 (22 atezolizumab/2 avelumab; [A]) and 12 received anti-PD1 (pembrolizumab [P]). 78% were men, median age 69 (46–81), 28% never smokers, 19% had prior intravesical BCG, 39% prior neoadjuvant chemotherapy, and 64% prior cystectomy. BOR to ICI included 3 PR/14 SD/7 PD (A) and 1 CR/2 PR/6 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC (mean change −5.26/dose; p = 0.009), while those of P correlated with decreased %PD1+ M- and I- MDSC (mean change −1.55 and −1.14/dose; p = 0.04 and 0.02, respectively). Though pre-tx %PD1+ CD8+ T cells did not predict BOR, greater PD1 expression by CD8+ T cells within 12 weeks after ICI initiation correlated with BOR (Table). Conclusions: ICI tx correlated with distinct changes in PD1/PDL1 expression by specific peripheral immune cell subsets. Responders to ICI had higher % of PD1+ CD8+ T cells after ICI than non-responders, though pre-tx % were comparable between groups. Further validation of these and other potential blood/tissue biomarkers is ongoing. [Table: see text]

Serial measurements of myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (CI).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16005-e16005
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Sample Collection ◽  
Peripheral Blood Mononuclear ◽  
Signed Rank ◽  
Metastatic Setting ◽  
Never Smokers ◽  
Ecog Ps

e16005 Background: MDSC are a heterogeneous population of immunosuppressive cells with potentially predictive implications in UC pts receiving CI. We hypothesized that MDSC populations may change after CI exposure. Methods: Serial peripheral blood samples were collected from mUC pts treated with CI. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. The Wilcoxon signed rank and rank sum tests were used to assess changes in MDSC populations while on CI. Results: 17 pts treated with CI (9 atezolizumab [A], 8 pembrolizumab [P]) had ≥ 2 MDSC samples for analysis. Median age at diagnosis was 71 (46-81), 12 men, 29% never smokers; 53% / 29% / 18% ECOG PS 0/1/2 and 59% visceral metastasis at the time of 1st sample collection. 10 pts received CI as 1st line therapy (Tx) in metastatic setting; 7 pts received chemotherapy as 1st-line Tx for mUC (6 platinum-based, 1 docetaxel) and CI as 2nd-line Tx. In 16 pts with samples before 1stdose, there was a relative decrease (median 36.3%, range -59.7 to +21.2) in PBMC % I-MDSCs between 1st and 2nd samples (p=0.06). Interestingly, PBMC %M-MDSC and %I-MDSC tended to increase compared to baseline in pts treated with P, while they tended to decrease in pts treated with A (Table). Conclusions: In this cohort of pts with mUC treated with CIs,MDSC changes differed based on CI (anti-PDL1 or anti-PD1). Further study in larger cohort with various prior Tx lines and longer follow up as well as correlations with Tx response, toxicity and outcomes are ongoing. [Table: see text]

Myeloid-Derived Suppressor Cells in Patients with Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3662-3662
Author(s):  
Nunziatina Parrinello ◽  
Piera La Cava ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Orazio Di Bartolo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Suppressor Cells ◽  
Cell Number ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr

Abstract Abstract 3662 Poster Board III-598 Background Immune suppression and angiogenesis are mechanisms key to tumour growth and progression. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin and include immature macrophages, dendritic cells (DC) and other myeloid cells. In mice are phenotypically characterized as CD11b+Gr-1+ cells, while in human they have an immature phenotype, including lineage negative (Lin-), CD14-, HLA-DR-, CD15+, CD34+, CD11b+, CD33+, and CD13+ cells. MDSC reduce activated T-cell number and inhibit their function through different mechanisms including: L-arginine metabolism, nitric oxide (NO), up-regulation of reactive oxygen species (ROS), and secretion of immunosuppressive cytokines. MDSC also promote tumor-dependent angiogenesis as well as tumor metastasis. Their accumulation has been described in patients affected by some solid tumors but information on haematological neoplasms are lacking. Our study investigated by flow cytometry the presence of MSDC in the peripheral blood of patients affected by Hodgkin Lymphoma (HL). Methods We studied 14 patients with HL at diagnosis and 10 age-matched healthy controls (HC). Peripheral blood mononuclear cells were stained with the following monoclonal antibodies:CD11b, CD13, CD14, CD34, CD45, for 20 minutes at room temperature. After lysing red cells, cells were analyzed by flow cytometry. Results we observed a increased number of MDSC (CD11b+,CD13+,CD34+,CD14-, CD45+) in the peripheral blood of patients with HL compared to HC (13,37 ± 17,77 ×109/l vs 1,45± 0,98 ×109/l, p=0,0007). We also found that patients with advanced-stage Hodgkin disease (III and IV) have higher number of MDSC, compared to patients stage I and II (p= 0,04). Conclusion These data suggest a role for myeloid-derived suppressor cells in promoting tumor cell proliferation in hodgkin lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Cytomegalovirus Infection and Genetic Background on the Frequencies of Peripheral Blood Suppressor Cells in Human Twins

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 963
Author(s):  
David Goldeck ◽  
Lisbeth Aagaard Larsen ◽  
Kaare Christensen ◽  
Klaus Hamprecht ◽  
Lilly Öttinger ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Genetic Background ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Minor Role ◽  
Peripheral Blood Mononuclear ◽  
Disease States ◽  
A Minor

Frequencies and proportions of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in peripheral blood may be informative biomarkers for certain disease states. The influence of genetics and lifetime pathogen exposures on Treg and MDSC frequencies is largely unexplored. Cytomegalovirus (CMV) establishes a latent infection and causes an accumulation of late-differentiated CD8+ memory T cells, commonly associated with a lower frequency of naive cells. Here, analyzing peripheral blood mononuclear cells by multicolor flow cytometry, we found a tendency towards lower frequencies of CD4+CD25+FoxP3+ Tregs in CMV-seropositive than -seronegative middle-aged individuals (p = 0.054), whereas frequencies of lineage-negative CD14+HLA-DR-MDSCs were significantly lower in CMV-seropositive participants (p = 0.005). Assessing associations with the presence of antibodies against different CMV structural proteins, rather than merely assigning seropositivity or seronegativity, failed to yield any closer associations. Examining Treg subsets revealed at most a minor role of the individual’s genetic background, based on an analysis of monozygotic (MZ, n = 42) versus dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry. The same was true for MDSCs. These initial results suggest that an immunological history of exposures is more important than genetics in determining overall human suppressor cell levels.

scholarly journals Detection of Brucellae in peripheral blood mononuclear cells for monitoring therapeutic efficacy of brucellosis infection

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Heng Yang ◽  
Guoxia Zhang ◽  
Peifang Luo ◽  
Zuoping He ◽  
Feihuan Hu ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Significant Risk ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Brucellosis ◽  
Sensitive Assay ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Blood Mononuclear Cells

Abstract Background Brucellosis is one of the most severe widespread zoonoses caused by the Gram-negative bacterium Brucella species. The diagnosis and clinical assessment of human brucellosis are very important for the management of patients, while there is a lack of effective methods to detect Brucellae. Classical culture of Brucella species is time consuming and often fails. A simple and sensitive assay is needed for diagnosis of Brucella infection and monitoring of treatment in man. Methods Blood samples and peripheral blood mononuclear cells (PBMCs) were collected from 154 patients hospitalized for brucellosis. Brucella antibodies were detected by Rose Bengal Plate Test (RBPT), Standard Tube Agglutination Test (SAT) and enzyme-linked immunosorbent assay (ELISA). Intracellular Brucellae were detected by blood culture and immunofluorescence staining (IFS). Results Among 154 brucellosis patients, 59.7% (92/154) were antibody reactive by RBPT, 81.8% (126/154) by SAT and 95.5% (147/154) by ELISA, respectively. Only 3.2% (5/154) of patient blood samples resulted in positive Brucella culture, while 68.8% (106/154) carried IFS detectable Brucella antigens in PBMCs. Gender (P = 0.01) but not age (P > 0.05) was a significant risk factor. The frequency of intracellular Brucella antigens was similar between patients receiving different treatment regimens (P > 0.05). However, a significant decrease of intracellular Brucellae was observed only in patients with acute brucellosis after the third course of treatment (P < 0.05), suggesting that current regimens to treat chronic brucellosis were not effective. Conclusions IFS appears a sensitive assay for detection of Brucella antigens in PBMCs and could be used for diagnosis and therapeutic monitoring of brucellosis in clinical practice.

scholarly journals Decreased Circulating Myeloid Derived Suppressor Cells at First Follow-up Predict Favorable Response to Immunotherapy in a Randomized Trial of Nivolumab and Bevacizumab in Recurrent GBM

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Matthew M Grabowski ◽  
Balint Otvos ◽  
Tyler J Alban ◽  
Marcella Diaz ◽  
Justin D Lathia ◽  
...  
Keyword(s):  
Treatment Response ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Single Cell Analysis ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunosuppressive Cell

Abstract INTRODUCTION A potential barrier to successful immunotherapy response in glioblastoma (GBM) is myeloid-derived suppressor cells (MDSCs): an immature immunosuppressive cell elevated in the circulation and tumor of GBM patients. Given a limited set of biomarkers predictive of response to immunotherapy in GBM, we explored the change in MDSC levels with immunotherapy to predict treatment response. METHODS A retrospective analysis was performed on patients in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence. Clinical and radiographic data were analyzed for disease progression or treatment response via Response Assessment in Neuro-Oncology (RANO) criteria. Blood was collected prior to treatment and at first imaging follow-up. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and analyzed. Characterization of circulating immune cells was performed using flow cytometry. RESULTS A total of 9 patients were identified as responders or nonresponders at a median time of 8.7 wk (range 6.9-10.0) after therapy initiation. MDSCs, as a percentage of total PBMCs, were elevated at baseline in responders compared to nonresponders (4.9% ± 0.7 vs 2.6% ± 0.2, P = .019), which reversed at follow up (1.8% ± 0.4 vs 5.8% ± 1.1, P = .032). There was a 6.4 fold decrease in MDSCs as a percentage of total PBMCs between baseline and first imaging follow-up in responders as compared to nonresponders (P = .001). When looking at subtypes of MDSCs, a 4.9 fold decrease in granulocytic MDSCs (G-MDSCs) was noted in responders over nonresponders (P = .010). Further investigation of this cohort by simultaneous single-cell analysis of transcriptome and surface epitopes is ongoing. CONCLUSION Differences in circulating MDSC levels that were specific to responders and nonresponders were seen both before and after therapy initialization, with decreases in MDSCs (specifically G-MDSCs) being correlated with treatment response. Characterization of MDSCs in the peripheral blood may be helpful in identifying GBM patients likely to benefit from immunotherapy.

Relationship of myeloid-derived suppressor cells (MDSC) and immune suppression, nutritional impairment, and inflammatory markers in patients with gastrointestinal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 675-675 ◽  
Author(s):  
Masahiko Shibata ◽  
Kenji Gonda ◽  
Izumi Nakamura ◽  
Shinji Ohki ◽  
Kenichi Sakurai ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Gastrointestinal Cancer ◽  
Peripheral Blood ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Cell Mediated Immunity ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Immune Suppressor Cells

675 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, have reported to be present in blood circulation in patients with cancer. MDSC have been reported to suppress immune function through several pathways. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers, and 53 patients with gastrointestinal cancer including 5 patients with esophageal, 16 with gastric, 26 with colorectal, 3 with bile duct, 1 with pancreatic and 1 with hepatocellular carcinomas, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI). Results: MDSC(%PBMC) of whole patients with gastrointestinal cancer, those with gastric cancer and those with colorectal cancer were higher than those of healthy volunteer (3.76+4.90%, 5.18+1.86%, 4.21+1.43% vs 1.59+1.08%, p<0.05, p<0.05, p<0.10, respectively). MDSC of patients with gastrointestinal cancer were also inversely correlated to the SI (r=−0.271, p<0.05) and to the serum concentrations of total protein (r=−0.490, p<0.005). It also tended to correlate to neutrophil counts (r=0.287, p<0.10) and neutrophil/lymphocyte ratios (NLR, r=0.623, p=0.10), and inversely did to lymphocyte counts (r=−0.251, p<0.10).Thus MDSC was successfully detected in peripheral blood and was significantly higher in patients with gastrointestinal cancer. It was related to the inhibition of cell-mediated immunity, hypoaproteinemia and inflammatory markers such as NLR. Conclusions: MDSC seemed to work in the mechanisms of suppression of immune reaction and malnutrition, typically seen in cancer cachexia, in patients with gastrointestinal cancer and may be important as a marker of advancement of malignant diseases.

Early proliferation of PD-1+ CD8 T cells in peripheral blood as predictive of response to PD-1 inhibition for patients with advanced NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20648-e20648
Author(s):  
Rathi Narayana Pillai ◽  
Alice O. Kamphorst ◽  
Shu Yang ◽  
Taofeek Kunle Owonikoko ◽  
Gabriel Sica ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nsclc Patient ◽  
Predictive Biomarkers ◽  
Fold Increase ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples

e20648 Background: Anti PD-1 and PDL-1 antibodies are now established immune targeted therapies for a subset of patients with advanced non-small cell lung cancer (NSCLC). There is a need for predictive biomarkers to better guide patient selection. We profiled peripheral blood samples from patients receiving PD-1 pathway targeted antibodies for lymphocyte subsets and correlated temporal changes with clinical response. Methods: NSCLC patients treated at our institution with PD-1 or PDL-1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) consented to an IRB-approved biomarker profiling protocol. We collected baseline peripheral blood samples before first treatment and subsequently prior to each new treatment cycle until progression of disease or for a maximum of six cycles. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for kinetics of proliferation of PD1+CD8+ T cells. Clinical response to anti PD-1 therapy was classified according to Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria and correlated with T cell proliferation kinetics. Results: We enrolled 27 patients with baseline characteristics: median age 66, male 70%, smokers 85%, adenocarcinoma 70%; 10 (37%) patients achieved partial response (PR), 7 (26%) had stable disease (SD) and 10 (10%) had disease progression (PD) as best response. There was a > 1.5-fold increase in Ki67+CD8+ T cells expressing PD-1 within 4 weeks of treatment initiation in 80% of patients with PR compared with 30% in patients with SD and 30% in those with PD. Conclusions: Early proliferation of PD1+CD8+ T cells in peripheral blood is a potential pharmacodynamic biomarker of anti PD-1 immunotherapy that could serve as a tool to identify the NSCLC patient subset most likely to respond to PD-1 and PDL-1 inhibitors.

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