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 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 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 Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

scholarly journals Combining PARP inhibition, radiation, and immunotherapy: A possible strategy to improve the treatment of cancer?

2018 ◽  
Vol 19 (12) ◽  
pp. 3793 ◽  
Author(s):  
Mathieu Césaire ◽  
Juliette Thariat ◽  
Serge M. Candéias ◽  
Dinu Stefan ◽  
Yannick Saintigny ◽  
...  
Keyword(s):  
Immune Response ◽  
Radiation Therapy ◽  
T Lymphocytes ◽  
Ionizing Radiation ◽  
Cytotoxic T Lymphocytes ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Antitumor Immune Response ◽  
Parp Inhibition

Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of improving the efficacy of immunotherapy. Because the value of immunotherapy is amplified with the expression of tumor antigens, coupling poly(ADP-ribose) polymerase (PARP) inhibitors and immunotherapy might be a promising treatment for cancer. Further, PARP inhibitors (PARPis) are being combined with radiation therapy to inhibit DNA repair functions, thus enhancing the effects of radiation; this association might interact with the antitumor immune response. Cytotoxic T lymphocytes are central to the antitumor immune response. PARP inhibitors and ionizing radiation can enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, but they can also enhance PD-1/PDL-1 expression. Thus, the addition of immune checkpoint inhibitors with PARP inhibitors and/or ionizing radiation could counterbalance such immunosuppressive effects. With the present review article, we proposed to evaluate some of these associated therapies, and we explored the biological mechanisms and medical benefits of the potential combination of radiation therapy, immunotherapy, and PARP inhibitors.

Novel heteroclitic XBP1 peptides evoking antigen-specific cytotoxic T lymphocytes targeting various solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3067-3067
Author(s):  
Jooeun Bae ◽  
Ruben Carrasco ◽  
John Daley ◽  
Glen Dranoff ◽  
Kenneth Carl Anderson ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Solid Tumors ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
Solid Tumor ◽  
Ex Vivo ◽  
Effector Memory ◽  
Repeated Stimulation ◽  
Hypoxic Conditions ◽  
The Unfolded Protein Response

3067 Background: Activation of the unfolded protein response (UPR) allows for tumor cells to survive prolonged endoplasmic reticulum stress and hypoxic conditions. XBP1 is an upstream element and a critical transcriptional activator of the UPR, and its up-regulation in a variety of human solid tumor cancers makes it as a promising immunotherapeutic target. The purpose of these studies was to evaluate immunogenic HLA-A2 XBP1-specific peptides for their ability to elicit cytotoxic T lymphocytes (CTL) against a variety of solid tumor cell lines. Methods: Upon the validation of XBP1 peptides for their strong HLA-A2 bindings and stabilities, peptide-specific CTL were generated ex vivo by repeated stimulation of CD3+ T lymphocytes obtained from HLA-A2+normal donors with XBP1 peptides-pulsed antigen-presenting cells, either dendritic cells or T2 cells. Results: A cocktail of heteroclitic XBP1 US184-192 (YISPWILAV) and heteroclitic XBP1 SP367-375 (YLFPQLISV) peptides with significantly improved HLA-A2 affinity and stability from their native counterparts were used to evoke XBP1 antigen-specific CTL. The CTL were predominantly CD3+CD8+ T cells (>80%) containing a high percentage of Effector Memory (EM; CCR7-CD45RO+) cells, which were distinctively evoked by repeated stimulation with the XBP1 peptides. In addition, the XBP1-CTL displayed a high level of cellular activation (CD69+/CD3+CD8+). The XBP1-CTL demonstrated effective anti-tumor responses including cell proliferation and IFN-g production, as well as degranulation (cytotoxic activity) against HLA-A2+breast cancer (MB231, MCF7), colon cancer (LS180, SW480) and pancreatic cancer (8902, Panc1, PL45) cell lines, which over-express both unspliced and spliced XBP1 antigens. Importantly, the specific anti-tumor activities were detected primarily in the EM CTL subset. Conclusions: These results suggest the immunotherapeutic potential of a cocktail of heteroclitic XBP1 US184-192 and XBP1 SP367-375 peptides to elicit effective anti-tumor responses against various solid tumors, and provide the framework for clinical development of vaccine trials to improve patient outcome.

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 Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3841
Author(s):  
Diana P. Saraiva ◽  
Sofia Azeredo-Lopes ◽  
Ana Antunes ◽  
Rute Salvador ◽  
Paula Borralho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Ex Vivo ◽  
Probability Model ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Effective Response ◽  
Hla Dr ◽  
Potential Biomarker

Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.

Induction of secondary cytotoxic T lymphocytes by liposomes containing HLA-DR antigens

Nature ◽  
1980 ◽  
Vol 283 (5746) ◽  
pp. 495-497 ◽  
Author(s):  
Steven J. Burakoff ◽  
Victor H. Engelhard ◽  
James Kaufman ◽  
Jack L. Strominger
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Hla Dr
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