scholarly journals Changes in the immune status of patients with metastatic solid tumors during stereotactic radiation therapy: dependence on dose and amount of irradiated metastasis

2021 ◽  
Vol 67 (3) ◽  
pp. 391-396
Author(s):  
Anton Zozulia ◽  
Irina Baldueva ◽  
Sergei Novikov ◽  
Dmitrii Girdiuk ◽  
Natalia Emelianova ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
T Cell ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Malignant Tumors ◽  
Cell Immune Response ◽  
Immunological Parameters ◽  
Hla Dr ◽  
T Helpers ◽  
Higher Doses

Purpose. To evaluate immunological status in patients with metastatic forms of solid tumors before and at different intervals after stereotactic body radiation therapy (SBRT) of metastatic lesions depending on the dose and the number of irradiated metastasis. Materials and methods. A quantitative assessment and analysis of blood immunological parameters was conducted before irradiation, via 3-4 weeks and via 6-8 weeks after SBRT in patients with malignant tumors with oligometastases in the liver and lungs, in groups with a total focal dose (TFD ≤ 45 Gy ) and TFD> 45 Gy, and also in groups with irradiation of one metastases and two or more. All peripheral blood samples were analyzed by flow cytometry. Statistical analysis was performed using Friedman and Nemenyi criteria. Results. 3-4 weeks after the end of SBRT, when using higher doses (TFD> 45 Gy), we observed statistically significant increase of T-lymphocytes (CD3+CD19-); T-helpers (CD3+CD4+); activated T-helpers (CD3+CD4+HLA-DR+); activated cytotoxic T-lymphocytes (CD3+СD8+HLA-DR+). Decreasing of B-lymphocytes (CD3+CD19-) was observed in both dose groups (TFD ≤ 45 Gy and TFD > 45 Gy). We also noted the activation of the T-cell link of immunity both in the group with irradiation of one metastatic lesion, and in the group where 2 or more metastases were exposed to irradiation. Conclusion. Using of higher doses of SBRT is associated with a more activated antitumor T-cell immune response, while the analysis of groups of patients with different ammount of irradiated metastasis currently requires further research.

scholarly journals CHANGES IN THE IMMUNE STATUS OF PATIENTS WITH METASTATIC SOLID TUMORS DURING STEREOTACTIC RADIATION THERAPY

2020 ◽  
Vol 66 (3) ◽  
pp. 277-282
Author(s):  
Anton Zozulya ◽  
Sergey Novikov ◽  
Irina Baldueva ◽  
D. Girdyuk ◽  
Natalya Yemelyanova ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Malignant Tumors ◽  
Immunological Parameters ◽  
Stereotactic Radiation ◽  
Metastatic Lesions ◽  
Hla Dr ◽  
T Helpers

Purpose. To evaluate immunological status in patients with metastatic forms of solid tumors before and at different intervals after stereotactic body radiation therapy (SBRT) of metastatic lesions. Materials and methods. A quantitative assessment and analysis of blood immunological parameters was conducted before irradiation, after 3-4 weeks and 6-8 weeks after SBRT in patients with malignant tumors with oligometastases in the liver and lungs. All peripheral blood samples were analyzed by flow cytometry. Statistical analysis was performed using Friedman and Nemenyi criteria. Results. 3-4 weeks after the end of SBRT, we observed statistically significant increase of T-lymphocytes (CD3+CD19-); T-helpers (CD3+CD4+); activated T-helpers (CD3+CD4+HLA-DR+); activated cytotoxic T-lymphocytes (CD3+CD8+HLA-DR+) and decrease of B-lymphocytes (CD3-CD19+). Subsequently, after 6-8 weeks after the end of irradiation we detected decrease of T-lymphocytes (CD3+CD19-) and continuing increase in activated T-helpers (CD3+CD4+HLA-DR+) and activated cytotoxic T-lymphocytes (CD3+CD8+HLA-DR+). Conclusion. Thus, revealed dynamics of immunological parameters indicates the induction of the T-cell link of antitumor immunity against decreasing of indicators of humoral immunity.

scholarly journals Changes of immune status in patients with different PD-L1 expression after stereotactic body radiation therapy of oligometastasis

2021 ◽  
Vol 67 (6) ◽  
pp. 797-803
Author(s):  
Anton Zozulia ◽  
Irina Baldueva ◽  
Anna Artemeva ◽  
Sergei Novikov ◽  
Anastasiia Muravtseva ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Stereotactic Body Radiation Therapy ◽  
Malignant Tumors ◽  
Cell Immune Response ◽  
Stereotactic Body Radiation ◽  
Hla Dr ◽  
Regulatory Lymphocytes ◽  
T Helpers

Purpose. To study the influence of PD-L1 expression on the dynamics of immunological changes before and at different intervals after stereotactic body radiation therapy (SBRT) of metastatic lesions in patients with metastatic forms of solid tumors. Materials and methods. A quantitative assessment and analysis of blood immunological parameters was conducted before irradiation, via 3-4 weeks and via 6-8 weeks after SBRT in patients with malignant tumors with oligometastases in the liver or lungs, in groups with negative and positive expression of PD-L1. All peripheral blood samples were analyzed by flow cytometry. Statistical analysis was performed using Friedman and Nemenyi criteria. Results. 3-4 weeks after the end of SBRT in group CPS <1 we observed statistically significant increase of activated T-helpers (CD3+CD4+HLA-DR+), activated cytotoxic T-lymphocytes (CD3+СD8+HLA-DR+), T-lymphocytes (CD3+CD19-) and T-helpers (CD3+CD4+). Wherein, activated T-helpers and activated cytotoxic T-lymphocytes statistically significantly increased 6-8 weeks after SBRT compared with the study before irradiation. In group CPS> 1, we revealed statistically significant increase of activated T-helpers 6-8 weeks after and decrease of T-regulatory lymphocytes (CD4+CD25brightCD127low) 3-4 weeks after completion of SBRT compared with the study before radiotherapy. When we analyzed the indicators by the TPS index, most of the statistically significant changes were recorded in the group with negative expression (TPS <1): increasing of activated T-helpers and activated cytotoxic T-lymphocytes 3-4 weeks and 6-8 weeks after SBRT and  decreasing of T-regulatory lymphocytes 3-4 weeks after irradiation compared with the study before irradiation. Conclusion. Groups with negative PD-L1 expression (CPS <1 and TPS <1) are associated with a more activated antitumor T-cell immune response compared to patients with positive PD-L1 status (CPS≥1 and TPS≥1), however, further researches are needed.  

scholarly journals Assessment of CLA+T-cell subpopulations in the blood of patients with chronic dermatoses

2020 ◽  
Vol 96 (4) ◽  
pp. 22-31
Author(s):  
Alexander V. Patrushev ◽  
Alexey V. Samtsov ◽  
Vladimir Yu. Nikitin ◽  
Alexey V. Soukharev ◽  
Oksana P. Gumilevskaya ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
T Cell ◽  
T Lymphocytes ◽  
Lichen Planus ◽  
Cytotoxic T Lymphocytes ◽  
Relative Number ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Relationship ◽  
T Helpers

Background. CLA+T-cell are an important component of skin-associated lymphoid tissue, and thus determine the pathogenesis of many immuno-mediated dermatoses. Aims. Determine the relative number of CLA+T-cell subpopulations in the peripheral blood of patients with psoriasis, lichen planus and atopic dermatitis, as well as assess their impact on the severity of dermatoses. Materials and methods. We examined 82 patients with psoriasis aged 19 to 62 years, 54 patients with lichen planus (LP) aged 18 to 54 years, 44 patients with atopic dermatitis (AD) aged 18 to 44 years, as well as 20 practically healthy individuals aged 18 to 52 years who were admitted to the clinic for the removal of benign skin neoplasms. All patients underwent a standard clinical examination with the determination of indicators that characterize the severity of dermatosis: PASI (Psoriasis Area and Severity Index) for patients with psoriasis, IPSLP (index of prevalence and severity of lichen planus) for patients with lichen planus and SCORAD (Scoring of Atopic Dermatitis) for patients with atopic dermatitis. Defining subpopulations CLA+T-lymphocytes were carried out on a flow cytometer Cytomics FC500 by Beckman Coulter using appropriate combinations of direct monoclonal antibodies and isotopic controls. The groups were compared using the nonparametric Mann Whitney test, and the differences were considered significant at p0,05. To analyze the relationship between the severity of dermatosis and the relative content of subpopulations CLA+T-cells used Spearman's rank correlation coefficient. Results. In patients with psoriasis, a significant increase in the percentage of the total number of T-lymphocytes positive for CLA (CLA+CD3+) and T-helpers positive for CLA (CLA+CD4+) (p=0,002 and 8,5104, respectively), in patients with PL and AD only CLA+CD4+ lymphocytes (p=0,028 and 0,003, respectively). In the progressive period of psoriasis, a direct moderate correlation was found between the circulating subpopulation of cytotoxic T lymphocytes positive for CLA (CLA+CD8+) and the PASI index (rs=0,47; p0,001), in the acute period of AD between the CLA+CD3+ subpopulations and CLA+CD4+ cells and the SCORAD index (rs=0,53; p 0,001 and rs=0,57; p0,001, respectively). In PL, the severity of the course of dermatosis was not accompanied by any significant changes in the CLA-positive T-cell subpopulations. Conclusion. The results of the study confirmed the important role of CLA+T cell subpopulations in the development of chronic dermatoses. In all groups (psoriasis, LP and AD), an increase in the relative number of CLA+CD4+ T-helpers was noted compared with the control group. The relationship between the severity of psoriasis and the relative number of CLA+CD8+ cytotoxic T-lymphocytes, and the severity of AD with CLA+CD3+ and CLA+CD4+ T-helpers is also shown.

scholarly journals Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Pedro Marques ◽  
Sayka Barry ◽  
Eivind Carlsen ◽  
David Collier ◽  
Amy Ronaldson ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Aggressive Behaviour ◽  
Epithelial To Mesenchymal Transition ◽  
Neuroendocrine Tumours ◽  
Tumour Microenvironment ◽  
Gh3 Cells ◽  
Ki 67 ◽  
Mesenchymal Transition ◽  
Hla Dr

Abstract Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA CD3 TCB) for the treatment of CEA-expressing solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2549-2549 ◽  
Author(s):  
Ignacio Melero ◽  
Neil Howard Segal ◽  
Jose M. Saro Suarez ◽  
Willeke Ros ◽  
Maria Martinez Garcia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Single Agent ◽  
Dose Dependence ◽  
T Cell Infiltration ◽  
Hla Dr ◽  
Tumor Lesion ◽  
Plasma Cytokines ◽  
Activation Profile

2549 Background: CEA CD3 TCB (RO6958688) targets CEA on tumor cells and is agonistic for CD3e on T cells. In mouse models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and up-regulates the PD-1/PD-L1 pathway. Methods: Biodistribution was assessed in mice using SPECT/CT. Patient (pts) samples correspond to 2 dose-escalation studies in CEA+ solid tumors. Study 1 (S1): single agent weekly (qW) (0.052 to 600 mg, iv, n = 80), and Study 2 (S2): combination of RO6958688 qW (5 to 160 mg, iv) with 1200mg atezolizumab q3W (n = 38). Analytical methods: PK - population modeling approach; anti-drug antibodies (ADA) - ELISA; immunophenotyping in peripheral blood (PB) by flow cytometry (FCM), in pre- (BSL) and on-treatment (OT) biopsies by immunohistochemistry (IHC) and FCM; plasma cytokines - multiplex assays; PD-L1 - SP142 assay. Results: In mice, RO6958688 preferentially accumulated in CEA+ tumors. In pts with no ADAs tested thus far in both studies (S1 29; S2 21), RO6958688 showed near linear PK and exposure. In S1, OT biopsies demonstrated a statistically significant increase in density and activation profile of T cells (CD3: 2.6-fold, n = 21; CD3/CD8: 3.7 fold, n = 17; CD3/Ki67: 4-fold, n = 20; CD8/PD1: 1.7-fold, n = 15) without dose-dependence. In S2, preliminary data of T cell density (5-80mg) were similar to S1 (2-fold). In S1, a significant correlation was observed between treatment-induced tumor lesion reduction and increases of OT CD8/CD25 fluorescence intensity from BSL (p = 0.028). PD-L1 expression increased in OT biopsies in both studies. In S1, from week 4, a moderate expansion of activated CD8 T cells (HLA-DR/Ki67) but not of CD4, was detected in PB at doses > 60mg ( > 3.3 fold). Transient increases of several cytokines were seen in both studies with levels peaking within 24hrs. Conclusions: PK and PD results consistent with tumor inflammation and mechanism of action support that RO6958688 is the first tumor-targeted T cell bispecific to show intra-tumoral biological activity in pts with CEA+ solid tumors. Updated data will be presented. Clinical data are reported separately.

scholarly journals Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens.

1982 ◽  
Vol 156 (4) ◽  
pp. 1065-1076 ◽  
Author(s):  
W E Biddison ◽  
P E Rao ◽  
M A Talle ◽  
G Goldstein ◽  
S Shaw
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Hla Antigens ◽  
Surface Expression ◽  
T Cell Differentiation ◽  
T Cell Recognition ◽  
Hla Dr ◽  
Specific Cytotoxicity ◽  
Functional Involvement

A recently described HLA gene, SB, which maps between GLO and HLA-DR, codes for Ia-like molecules that are similar to but distinct from HLA-DR molecules. Cytotoxic T lymphocytes (CTL) specific for SB1, SB2, SB3, and SB4 were compared with HLA-A2-specific CTL with respect to their surface expression of the T cell differentiation antigens OKT3, OKT4, and OKT8. All CTL activity was eliminated by treatment with OKT3 and C'. The SB-specific cytotoxicity was eliminated by OKT4 plus C' but not by OKT8 plus C'. In contrast, HLA-A2-specific killing was completely susceptible to treatment with OKT8 plus C' but not with OKT4 plus C'. Cytotoxicity was analyzed in the presence of OKT8 and a series of monoclonal antibodies (OKT4A, 4B, 4C, and 4D) that react with distinct epitopes on the OKT4 molecule. SB1-, SB3-, and SB4-specific CTL were partially inhibited by OKT4A and 4B (45-75%), whereas HLA-A2-specific CTL were partially inhibited by OKT8 (48-63%) but not by OKT4. SB2-specific CTL were not inhibited (less than 26%) by OKT8 or by any of the OKT4-related antibodies. These results suggest that the OKT4 marker may be expressed on most T cells that recognize allogeneic Ia or self Ia plus foreign antigens; OKT4+ cells do not appear to be functionally homogeneous in that they can act both as helper/inducer and cytotoxic cells. Models are proposed for the functional involvement of the OKT4 molecule in T cell-Ia antigen interactions.

scholarly journals Cancer immunotherapy: current opportunities and perspectives

2021 ◽  
Vol 4 (2) ◽  
pp. 25-38
Author(s):  
O.Yu. Nikolaeva ◽  
R.V. Liubota ◽  
O.S. Zotov ◽  
R.I. Vereshchako
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Anticancer Agents ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Focus

Cancer immunotherapy is a relatively new and pro­mising method of treating neoplasms. Understanding the antigen-directed cytotoxicity of T-lymphocytes has become one of the central directions in involving the immune system in the fight against cancer. Basic research in this area has led to the invention of checkpoint inhibitors, adoptive T-cell therapy, and cancer vaccines. Cytokines can enhance the action of T-lymphocytes for their ability to directly stimulate effector and stromal cells in tumor focus and enhance recognition of tumor cells by cytotoxic effector cells. They were the first in cancer immunotherapy and remain relevant to this day. Today, immunotherapy is an effective treatment for most malignant tumors, including melanoma, non-small cell lung cancer, liver, stomach, bladder, cervical cancer, some types of breast cancer, lymphoma, etc. However, immunotherapy of some malignant tumors is ineffective, therefore, the development of new and improvement of existing immunotherapy agents is actively underway, and there is a hope that the indications for its use will expand. For this purpose, this review discusses the principles of action of various classes of immunotherapeutic anticancer agents, namely cytokines, immune checkpoint inhibitors, and adaptive T-cell therapy. The work highlights their indications, efficacy and toxicity from the use of each class of drugs, as well as the prospects for the development of immunotherapeutic anticancer drugs.

Myeloid Impairment Contributes to Immunoparesis in Multiple Myeloma but Not MGUS

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1831-1831
Author(s):  
Alessandra Romano ◽  
Nunziatina Parrinello ◽  
Calogero Vetro ◽  
Piera La Cava ◽  
Annalisa Chiarenza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Conflicts Of Interest ◽  
Myeloid Suppressor Cells ◽  
Hla Dr ◽  
Healthy Donors

Abstract Abstract 1831 Introduction In Multiple Myeloma (MM), but not in the monoclonal gammopathy of unknown significance (MGUS), the immune function is impaired as consequence of an immunologically hostile microenvironment and cellular defects, including reduction of immuno-surveillance and T-cell immunoparesis. We conducted an study focused on the myeloid compartment in MM, and its role in the progression from MGUS to MM. Methods Between January 2009 and April 2011 peripheral blood obtained from 60 consecutive newly diagnosed MM and 70 MGUS plus 30 healthy subjects was studied for evaluation of myeloid subpopulations and lymphoid paresis. Myeloid dysfunction was evaluated as percentage and absolute count of circulating myeloid suppressor cells (MDSC) in peripheral blood assessed by flow cytometry as follows: im-MDSC (CD34+/CD11b+/CD13+/CD14-/ HLA-DR-/CD45+), neutrophilic-like N-MDSC (CD11b+/CD13+/CD15+/CD14-/HLA-DR-/Lin-) and monocytic-like mo-MDSC (CD14+/HLA-DRlow/-). Myeloid function was evaluated by phagocytic activity using a commercially available kit (Phagotest R). Further, we investigated whether MM-neutrophils were able to induce anergy in T-cells. Neutrophils isolated from healthy donor (N=6), MGUS (N=3) or MM (N=6) peripheral blood (PB) were co-cultured with T-lymphocytes obtained from healthy donors. Expression of markers of activation in response to stimulation with PHA-P for 2 hours was assessed by flow cytometry as antigen density expressed as normalized mean of fluorescence intensity (N-MFI) of CD71 at 48 hours. Results The capability of phagocytosis of in neutrophils and monocytes from MM patients at diagnosis was significantly reduced compared to healthy subjects (p<0.001) and MGUS (p<0.0001). While the mature suppressive N-MDSC subset was not increased in MGUS and MM patients, the mo-MDSC subpopulation showed an increasing trend from healthy donors through MM (p=0.06) and the im-MDSC subset was significantly higher in MM vs healthy (p=0.002) and MGUS (p=0.001). After PHA-P stimulation, expression of CD71 (a marker of activation) in normal T-lymphocytes was increased (2954 ± 240.6 arbitrary units, au), and it was reduced (751.3 ± 30.48 au, p=0.0001) when co-coltured with MM-neutrophils, while no differences were evident in co-colture with MGUS- (2783 ± 206.1 au, p=0.61) or healthy donors-neutrophils (2588 ± 135.4, p=0.38). Conclusion Taken together, our findings suggest that in MM but not in MGUS there is a myeloid cell dysfunction that is correlated to impairment of T- cell arm. These alterations may have a role in the development of MM. Disclosures: No relevant conflicts of interest to declare.

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