scholarly journals Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: Results from a Single-Institution Retrospective Analysis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 213
Author(s):  
Ilario Giovanni Rapposelli ◽  
Serena De Matteis ◽  
Paola Lanuti ◽  
Martina Valgiusti ◽  
Giulia Bartolini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Response Assessment ◽  
Complete Response ◽  
Lower Percentage ◽  
Peripheral Blood Mononuclear ◽  
Heterogeneous Behavior ◽  
New Perspective

Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.

scholarly journals IMMU-18. IMMUNOGENOMIC RESPONDER PHENOTYPE FROM A PHASE I TRIAL OF ANTI-LAG3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi122-vi123
Author(s):  
Christina Jackson ◽  
John Choi ◽  
JiaJia Zhang ◽  
Anna Piotrowski ◽  
Tobias Walbert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Lower Percentage ◽  
Radiographic Evaluation ◽  
Peripheral Blood Mononuclear ◽  
Initial Resection

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are not uniformly effective in glioblastoma treatment. Immunogenomic determinants may identify patients who are most likely to benefit from these therapies. Therefore, we compared the immunogenomic phenotype of a responder to combination anti-LAG-3 and anti-PD-1 therapy to non-responders. METHODS We performed T cell receptor (TCR) sequencing and gene expression analysis on pre-treatment, post-chemoradiation, and post-immunotherapy tumor specimens of glioblastoma patients treated with anti-LAG3 in combination with anti-PD-1 after first recurrence (NCT02658981, ongoing). We evaluated T cell clonotypes and immunophenotype of serially collected peripheral blood mononuclear cells (PBMCs) during treatment using multi-parametric flow cytometry. RESULTS To date, six patients have been enrolled in the initial anti-LAG-3 and anti-PD-1 cohort. One patient demonstrated complete response, one had stable disease, and four had progressive disease by radiographic evaluation. The responder demonstrated substantially higher TCR clonality in the resected tumor at initial diagnosis compared to non-responders (mean 0.028 vs. 0.005). Shared tumor infiltrating clonotypes with pre-immunotherapy PBMCs exhibited an increase in frequency from initial resection (6.8%) to resection at recurrence (20%). The responder’s tumor at initial resection exhibited increased gene signatures of PD1low CD8+ T cells, chemokine signaling, and interferon gamma pathways. On PBMC phenotypic analysis, the responder demonstrated significantly higher percentages of CD137+ CD8+T cells (median 8.38% vs 3.24%, p=0.02) and lower percentages of Foxp3+CD137+ CD4+T cells compared to non-responders (median 18.5% vs. 38.5%, p=0.006). Interestingly, dynamic analysis of PBMCs showed that the responder demonstrated a lower percentage of PD1+ CD8+ T cells pre-immunotherapy (median 2.5% vs.12.4%, p=0.002), with persistent decrease over the course of treatment while non-responders showed no consistent pattern. CONCLUSION Our preliminary results demonstrate significant differences in tumor and peripheral blood immunogenomic characteristics between responder and non-responders to anti-LAG3 and anti-PD-1 therapy. These immunogenomic characteristics may help stratify patients’ response to combination ICIs.

scholarly journals Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the clonal level

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 956-963
Author(s):  
GC Barbano ◽  
A Schenone ◽  
S Roncella ◽  
R Ghio ◽  
A Corcione ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Recombinant Interleukin 2 ◽  
Macrophage Colony

Abstract Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with anti-lymphocyte globulin (ALG), and the phenotypic and functional properties of the blasts obtained were investigated. When stained with monoclonal antibodies (MoAbs), all of the blasts were identified as T cells that expressed predominantly the CD4 phenotype (70% of the cells). The remaining blasts were CD8+. These findings demonstrate that ALG stimulates both helper-inducer and cytotoxic- suppressor cells at random since the CD4 to CD8 ratio in the stimulated blasts was the same as in resting PBMC. This ratio is different from that observed in short-term cultures of T cells stimulated with phytohemagglutinin (PHA) under the same conditions (CD4 to CD8 ratio less than 1). ALG-stimulated T cells were cloned by limiting dilution in the presence of recombinant Interleukin-2 (rIL-2). The clones obtained were expanded and maintained in long term cultures with rIL-2. Thirty-two clones were tested for their capacity of producing colony stimulating activity (CSA) or burst promoting activity (BPA). Twenty- eight of them produced CSA and 12 produced BPA. No correlation was found between the surface phenotype and the ability of the clones to produce CSA or BPA (ie, both the CD4+ and CD8+ clones released the cytokines). When 16 of the same clones were tested for II-2 and gamma interferon (gamma IFN) production, 12 were found to be gamma INF and IL- 2 producers. All of the gamma IFN producers also released IL-2, whereas in the single clones no correlation was found with the capacity of releasing BPA and CSA. Supernatants from selected T-cell clones were also tested for hematopoietic growth factor activities in the presence of neutralizing antisera to human granulocyte-macrophage colony stimulating factor (GM-CSF) or to Interleukin-3 (IL-3). It was found that most CSA was attributable to GM-CSF, whereas BPA was mainly related to the presence of IL-3.

scholarly journals The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing

2020 ◽  
Author(s):  
Gang Xu ◽  
Furong Qi ◽  
Hanjie Li ◽  
Qianting Yang ◽  
Haiyan Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Close Association ◽  
Suppressor Cells ◽  
T Cell Subsets ◽  
Peripheral Blood Mononuclear ◽  
Peripheral T Cells

Understanding the mechanism that leads to immune dysfunction induced by SARS-CoV2 virus is crucial to develop treatment for severe COVID-19. Here, using single cell RNA-seq, we characterized the peripheral blood mononuclear cells (PBMC) from uninfected controls and COVID-19 patients, and cells in paired broncho-alveolar lavage fluid (BALF). We found a close association of decreased dendritic cells (DC) and increased monocytes resembling myeloid-derived suppressor cells (MDSC) which correlated with lymphopenia and inflammation in the blood of severe COVID-19 patients. Those MDSC-like monocytes were immune-paralyzed. In contrast, monocyte-macrophages in BALFs of COVID-19 patients produced massive amounts of cytokines and chemokines, but secreted little interferons. The frequencies of peripheral T cells and NK cells were significantly decreased in severe COVID-19 patients, especially for innate-like T and various CD8+ T cell subsets, compared to health controls. In contrast, the proportions of various activated CD4+ T cell subsets, including Th1, Th2 and Th17-like cells were increased and more clonally expanded in severe COVID-19 patients. Patients' peripheral T cells showed no sign of exhaustion or augmented cell death, whereas T cells in BALFs produced higher levels of IFNG, TNF, CCL4 and CCL5 etc. Paired TCR tracking indicated abundant recruitment of peripheral T cells to the patients' lung. Together, this study comprehensively depicts how the immune cell landscape is perturbed in severe COVID-19.

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 Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the clonal level

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 956-963 ◽  
Author(s):  
GC Barbano ◽  
A Schenone ◽  
S Roncella ◽  
R Ghio ◽  
A Corcione ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Recombinant Interleukin 2 ◽  
Macrophage Colony

Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with anti-lymphocyte globulin (ALG), and the phenotypic and functional properties of the blasts obtained were investigated. When stained with monoclonal antibodies (MoAbs), all of the blasts were identified as T cells that expressed predominantly the CD4 phenotype (70% of the cells). The remaining blasts were CD8+. These findings demonstrate that ALG stimulates both helper-inducer and cytotoxic- suppressor cells at random since the CD4 to CD8 ratio in the stimulated blasts was the same as in resting PBMC. This ratio is different from that observed in short-term cultures of T cells stimulated with phytohemagglutinin (PHA) under the same conditions (CD4 to CD8 ratio less than 1). ALG-stimulated T cells were cloned by limiting dilution in the presence of recombinant Interleukin-2 (rIL-2). The clones obtained were expanded and maintained in long term cultures with rIL-2. Thirty-two clones were tested for their capacity of producing colony stimulating activity (CSA) or burst promoting activity (BPA). Twenty- eight of them produced CSA and 12 produced BPA. No correlation was found between the surface phenotype and the ability of the clones to produce CSA or BPA (ie, both the CD4+ and CD8+ clones released the cytokines). When 16 of the same clones were tested for II-2 and gamma interferon (gamma IFN) production, 12 were found to be gamma INF and IL- 2 producers. All of the gamma IFN producers also released IL-2, whereas in the single clones no correlation was found with the capacity of releasing BPA and CSA. Supernatants from selected T-cell clones were also tested for hematopoietic growth factor activities in the presence of neutralizing antisera to human granulocyte-macrophage colony stimulating factor (GM-CSF) or to Interleukin-3 (IL-3). It was found that most CSA was attributable to GM-CSF, whereas BPA was mainly related to the presence of IL-3.

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]

Alteration in mononuclear cell subpopulations in dogs immunized with gentamicin-attenuatedLeishmania infantum

Parasitology ◽  
2012 ◽  
Vol 139 (13) ◽  
pp. 1689-1696 ◽  
Author(s):  
HAMID DANESHVAR ◽  
FARNAZ SEDGHY ◽  
SHAHRIAR DABIRI ◽  
HOSSEIN KAMIABI ◽  
MOHAMMAD M. MOLAEI ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Mononuclear Cells ◽  
Lower Percentage ◽  
Wild Type ◽  
Peripheral Blood Mononuclear ◽  
Mhc Ii ◽  
Blood Mononuclear Cells ◽  
Cell Subpopulations ◽  
The Impact

SUMMARYThe impact of immunization with gentamicin-attenuatedLeishmania infantum(H-line) on the immunophenotypic profile of popliteal lymph node (PLN) and peripheral blood mononuclear cells (PBMCs) of dogs was assessed by flow cytometry and immunohistochemistry. Compared with the dogs infected withL. infantumwild-type (Group WT), there was a significantly higher percentage of CD4+, CD44+T cells and CD14+, MHC-II+cells and a lower percentage of CD4+CD25+regulatory T cells in PLN of the immunized dogs withL. infantumH-line (Group H). The percentage of CD4+and CD8+T cells in PBMCs of immunized dogs was higher than that in dogs of Group WT. The CD4:CD8 ratio in PLN of dogs of Group H was significantly higher than that in dogs of Group WT. A significantly higher percentage of CD21+B cells and a lower percentage of CD79b+cells were found in PLN of the immunized dogs compared with dogs of Group WT. Immunohistochemical investigation showed no parasites in the PLN of immunized dogs whereas there were parasites in the PLN of 60% of dogs infected withL. infantumWT. In this study, the immunophenotypic profile of mononuclear cells of the immunized dogs correlates with cellular immunity.

Correlation of myeloid-derived suppressor cells (MDSC) with pathologic complete response (pCR), recurrence free survival (RFS), and overall survival (OS) in patients with urothelial carcinoma (UC) undergoing cystectomy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 437-437
Author(s):  
Jaleh Fallah ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Wei (Auston) Wei ◽  
Iris Yeong- Fung Sheng ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Pathologic Complete Response ◽  
Suppressor Cells ◽  
Complete Response ◽  
Rank Test ◽  
Peripheral Blood Mononuclear ◽  
One Year ◽  
Circulating Levels

437 Background: MDSCs play an important role in maintaining a tumor immunosuppressive microenvironment. The association of circulating levels of MDSCs with pCR (pT0N0) and outcomes was investigated in patients (pts) with non-metastatic UC undergoing cystectomy. Methods: Peripheral blood samples from pts with non-metastatic UC was collected. MDSCs were measured in freshly purified peripheral blood mononuclear cells, using flow cytometry. Total (T) MDSC was defined as CD33+/HLADR-. T-MDSC subtypes were polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+], and uncommitted (UC-MDSC: CD15-/CD14-]. MDSC populations were presented as % of live nucleated blood cells. Wilcoxon rank sum test was used to compare MDSCs between pCR groups. Kaplan-Meier and log-rank test were used to analyze RFS and OS. Results: MDSC data were available for 124 pts (106 male, 18 female), median age 68, 28 (23%) never smokers, 93 (75%) pure UC. Thirty four pts (27%) received intravesical BCG; 49 (39%) received neoadjuvant chemotherapy (NAC); 22 (19%) had pCR (pT0N0) following surgery. PMN-MDSC was the dominant subtype (42%) and frequency of UC-MDSC and M-MDSC was 40% and 17%, respectively. Circulating levels of T-MDSC and PMN-MDSC were significantly lower in pCR patients than those in non-pCR patients (Table). Sixteen deaths were observed and 21 pts recurred after surgery. The median follow-up time of patients alive was 18.7 months (range 0.3-42.4). The median OS or RFS of all patients was not reached. One-year and two-year OS rates were 94% and 83%, respectively. One-year and two-year RFS rates were 82% and 69%, respectively. There was no association between MDSC subtypes with OS or RFS. Conclusions: Total- and PMN-MDSC subtypes in blood were significantly correlated with pCR in pts with non-metastatic UC who undergo cystectomy. The relatively short follow-up may impact the association with RFS and OS; additional follow-up is needed. [Table: see text]

scholarly journals Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 627 ◽  
Author(s):  
Nada Chaoul ◽  
Serena Mancarella ◽  
Luigi Lupo ◽  
Gianluigi Giannelli ◽  
Francesco Dituri
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Immune Cell Subsets ◽  
Memory Cd4 T Cells

Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the perspective of immunotherapy. After obtaining single cell suspensions from freshly collected specimens of HCC tumor, along with paired peritumor tissues and peripheral blood mononuclear cells (PBMCs) from 14 patients, we flow-cytometrically identified and quantified the relative frequencies of lymphocyte subsets within the tissues of origin. We found that the recruitment in the tumor of cytotoxic cells, namely the terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired, whereas the effector memory CD4+ T cells (TEM) are more attracted in this site. Concerning the other subsets, the frequency of NK CD56hi and NKT CD56hi cells infiltration in the tumor is increased, whereas that of NKT CD56low is reduced. Although CD4+ and CD8+ T cells settled in the tumor show a higher degree of activation than the circulating counterpart, they occur with a more exhausted phenotype. Overall, these data demonstrate the prevalently immunosuppressive nature of HCC microenvironment, and prompt us to search for strategies to enhance the activity of anti-tumor immune cell subsets.

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