Cellular immune suppression in cancer patients and its implication for dendritic cell therapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3028-3028 ◽  
Author(s):  
J. Nesselhut ◽  
D. R. Lorenzen ◽  
D. Marx ◽  
R. Y. Chang ◽  
C. Matthes ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Immune Suppression ◽  
Human Cancer ◽  
Metronomic Chemotherapy ◽  
Advanced Cancer Patients ◽  
Down Regulation ◽  
Antitumor Response ◽  
Healthy Donors

3028 Background: The treatment of human cancer with monocyte-derived dendritic cells (MoDC) is a promising and innovative approach. However, many of the treated patients fail to respond to therapy. The reduced clinical antitumor response may be due to an inflammatory immune-suppressive tumor microenvironment. Regulatory T-cells (T-reg) and other cells with suppressive potential can promote an immune suppressive tumor microenvironment and thus play an important role in regulation of the immune response. Methods: Whole blood from n=100 cancer patients with various tumor types and from n=30 healthy donors were analysed by flow cytometry. CD4+ lymphocytes with immune suppressive potential were characterized by analysing the expression of CD25, CD39, CD127. Results: We found a significantly higher proportion of CD25+/CD39+ and of CD25+/CD127low T-helper cells in the blood of cancer patients as compared to healthy donors. This may indicate two different types of T-reg involved in immune suppression in cancer patients. Treatment of patients with metronomic chemotherapy induced a down-regulation of these cells. Interestingly, we found a subpopulation of cells within the lymphocyte gate characterized by CD2high and CD86 expression in cancer patients with very advanced stage, similar to such normally found in hemaphagocytic lymphohistiocytosis (HLH) patients characterized by exceeding high plasma concentration of IFN-g and IL-10 (Schneider et al. 2002). These cells can be down-regulated by treatment with a tetradecapeptide (Ezrin) known to act as an immune modulator with anti-viral activity leading to reduction of inflammatory cytokines. Conclusions: An efficient induction of a clinical antitumor response requires both a polarization of MoDC in a TH1 direction as well as changing an immune suppressive tumor microenvironment. For the first time, we identified HLH associated cells in advanced cancer patients. As HLH is characterized by hyperinflammation, these cells may indicate an inflammatory tumor microenvironment. Thus, anti-inflammatory therapy should be considered as co-treatment with immunotherapy with dendritic cells for down-regulation of immune suppressive cells (T-reg, CD2high/CD86+ cells) to promote a clinical antitumor response. No significant financial relationships to disclose.

Induction of an antitumor response using dendritic cells transfected with DNA constructs encoding the HLA-A*02:01-restricted epitopes of tumor-associated antigens in culture of mononuclear cells of breast cancer patients

2015 ◽  
Vol 64 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Sergey Vital’evich Sennikov ◽  
Julia Alexandrovna Shevchenko ◽  
Vasilii Vasil’evich Kurilin ◽  
Julia Nikolaevna Khantakova ◽  
Julia Anatol’evna Lopatnikova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Breast Cancer Patients ◽  
Antitumor Response ◽  
Tumor Associated Antigens

scholarly journals Phenotypical and functional properties of generated dendritic cells in lung cancer patients

2016 ◽  
Vol 4 (2) ◽  
pp. 162-166 ◽  
Author(s):  
N. Khranovska ◽  
O. Skachkova ◽  
V. Sovenko ◽  
P. Sydor ◽  
M. Inomistova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Combined Treatment ◽  
Lower Amount ◽  
Functional Characteristics ◽  
Lung Cancer Patients ◽  
Healthy Donors ◽  
Dc Vaccines ◽  
Antitumor Vaccine

This study aimed to investigate phenotypical and functional characteristics of dendritic cells (DCs) generated from monocytes of peripheral blood of healthy donors and cancer patients.Material and methods. DCs were used as natural adjuvants with antitumor vaccine as a part of combined treatment scheme for lung cancer patients. Phenotypical and functional characteristics of DCs were study using flow cytometry and real-time PCR.Results. We have found that in lung cancer patients generated DCs had moderate level of maturity and demonstrated more pronounced tolerogenic features in contrast to DCs of healthy donors (patients DCs had higher mRNA expression levels of suppressive molecules TGF-β and IDO, and secreted lower amount of bioactive IL-12 protein). Expression of CCR7 gene was particularly on the normal level in DCs of cancer patients which indicates on saving of migratory properties of these cells. Expression level of DC maturity marker CD83 increased after each subsequent vaccine administration, while the levels of TGF-β, IL-10 mRNAs to the end of vaccine therapy course decreased to the level observed in healthy donors DCs.Conclusion. Thus, the study of biological characteristics of DCs will help to improve and develop the most effective protocols for rational use of DC vaccines. These data indicate the need for further optimization of technologies of DC generation in patients with lung cancer with emphasis on the stimulation of Th1-polarizing properties by increasing cytokine-secreting potential.

scholarly journals Could Increased Expression of Hsp27, an “Anti-Inflammatory” Chaperone, Contribute to the Monocyte-Derived Dendritic Cell Bias towards Tolerance Induction in Breast Cancer Patients?

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Ana Paula Silva de Azevedo-Santos ◽  
Mirtes Castelo Branco Rocha ◽  
Sulayne Janayna Araujo Guimarães ◽  
André Alvares Marques Vale ◽  
Fabio Martins Laginha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Chronic Inflammation ◽  
Lymphocyte Proliferation ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Surface Phenotype ◽  
Hsp27 Expression ◽  
Healthy Donors

Dendritic cells (DCs) are the most efficient antigen-presenting cells and link the innate immune sensing of the environment to the initiation of adaptive immune responses, which may be directed to either acceptance or elimination of the recognized antigen. In cancer patients, though DCs would be expected to present tumor antigens to T lymphocytes and induce tumor-eliminating responses, this is frequently not the case. The complex tumor microenvironment subverts the immune response, blocks some effector mechanisms, and drives others to support tumor growth. Chronic inflammation in a tumor microenvironment is believed to contribute to the induction of such regulatory/tolerogenic response. Among the various mediators of the modulatory switch in chronic inflammation is the “antidanger signal” chaperone, heat shock protein 27 (Hsp27), that has been described, interestingly, to be associated with cell migration and drug resistance of breast cancer cells. Thus, here, we investigated the expression of Hsp27 during the differentiation of monocyte-derived DCs (Mo-DCs) from healthy donors and breast cancer patients and evaluated their surface phenotype, cytokine secretion pattern, and lymphostimulatory activity. Surface phenotype and lymphocyte proliferation were evaluated by flow cytometry, interferon- (IFN-) γ, and interleukin- (IL-) 10 secretion, by ELISA and Hsp27 expression, by quantitative polymerase chain reaction (qPCR). Mo-DCs from cancer patients presented decreased expression of DC maturation markers, decreased ability to induce allogeneic lymphocyte proliferation, and increased IL-10 secretion. In coculture with breast cancer cell lines, healthy donors’ Mo-DCs showed phenotype changes similar to those found in patients’ cells. Interestingly, patients’ monocytes expressed less GM-CSF and IL-4 receptors than healthy donors’ monocytes and Hsp27 expression was significantly higher in patients’ Mo-DCs (and in tumor samples). Both phenomena could contribute to the phenotypic bias of breast cancer patients’ Mo-DCs and might prove potential targets for the development of new immunotherapeutic approaches for breast cancer.

Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients

2010 ◽  
Vol 59 (11) ◽  
pp. 1611-1619 ◽  
Author(s):  
Florian Cabillic ◽  
Olivier Toutirais ◽  
Vincent Lavoué ◽  
Cécile Thomas de La Pintière ◽  
Pascale Daniel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Advanced Cancer Patients

scholarly journals Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells

2008 ◽  
Vol 180 (11) ◽  
pp. 7287-7293 ◽  
Author(s):  
Hans J. J. van der Vliet ◽  
Ruojie Wang ◽  
Simon C. Yue ◽  
Henry B. Koon ◽  
Steven P. Balk ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Nkt Cells ◽  
Cytokine Profile ◽  
Advanced Cancer Patients ◽  
Myeloid Dendritic Cells ◽  
Invariant Nkt Cells

scholarly journals Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Fabian Benencia ◽  
Leslee Sprague ◽  
John McGinty ◽  
Michelle Pate ◽  
Maria Muccioli
Keyword(s):  
Clinical Trials ◽  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Dc Vaccines ◽  
Tumor Clearance ◽  
Antigen Presenting

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.

scholarly journals PENTOXIFYLLINE ENHANCES IN VITRO T-CELL ANTITUMOR RESPONSE IN BREAST CANCER PATIENTS

2021 ◽  
Vol 23 (4) ◽  
pp. 785-790
Author(s):  
M. S. Kuznetsova ◽  
J. A. Shevchenko ◽  
J. N. Khantakova ◽  
A. A. Khristin ◽  
I. A. Obleukhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Cell Activity ◽  
Metastatic Breast ◽  
Antitumor Response ◽  
Healthy Donors

The NF-κB transcription factor controls the expression of genes responsible for cell cycle, apoptosis, and other immunoregulatory functions. Some nonspecific NF-κB inhibitors were found after discovering the possibility of blocking tumor growth through suppression of NF-κB activity, but their use was complicated by multiple side effects, such as interleukin-1β-related systemic inflammation or non-immunerelated complications, which may be due to inhibition of the p65 NF-κB subunit that plays a central role in organogenesis and inflammation. Inhibition of the c-Rel subunit leads to tumor growth restriction by modulating the T-regulatory cell activity.In 2017, Grinberg-Bleyer and co-authors checked the hypothesis that selective inhibition of the c-Rel subunit can be performed using pentoxifylline and will effectively regulate Treg activity during tumor growth. The authors showed that pentoxphylline, an FDA-approved drug, could indeed induce selective degradation of c-Rel without affecting p65, and suggested that such an effect could be effective in suppressing tumor growth. In this regard, we aimed to investigate in vitro how pentoxifylline affect the functional activity and antitumor cytotoxic potential of T-cells in cancer patients.The objects of the study were peripheral blood mononuclear cells from 25 patients with primary breast cancer (no metastases), 15 patients with metastatic breast cancer, and 25 healthy women without breast pathology. Informed consent was obtained from all donors and patients. The study was approved by the local ethics committee.Here we showed that pentoxifylline treatment in vitro enhances the pro-apoptotic and cytotoxic antitumor response via increasing the expression of TRAIL on T-lymphocytes, mainly in healthy donors and patients with metastatic breast cancer, both on intact T-cells and in response to the cells of the tumor line of human breast carcinoma ZR-75-1. In healthy donors, in the presence of pentoxifylline, a population of highly expressing TRAIL CD4 and CD8 T-cells appears. 

scholarly journals Defective Differentiation of Myeloid and Plasmacytoid Dendritic Cells in Advanced Cancer Patients is not Normalized by Tyrosine Kinase Inhibition of the Vascular Endothelial Growth Factor Receptor

2007 ◽  
Vol 2007 ◽  
pp. 1-9 ◽  
Author(s):  
H. van Cruijsen ◽  
K. Hoekman ◽  
A. G. M. Stam ◽  
A. J. M. van den Eertwegh ◽  
B. C. Kuenen ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Dendritic Cells ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Advanced Cancer Patients ◽  
Endothelial Growth Factor

Tumor-derived vascular endothelial growth factor (VEGF) has previously been identified as a causative factor in the disturbed differentiation of myeloid dendritic cells (DC) in advanced cancer patients. Here, we investigated the potential of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase (TK) inhibition to overcome this defective DC differentiation. To this end, peripheral blood DC (PBDC) precursor and subset frequencies were measured in 13 patients with advanced cancer before and after treatment with AZD2171, a TK inhibitor (TKI) of VEGFR, coadministered with gefitinib, and an epidermal growth factor receptor (EGFR) TKI. Of note, not only myeloid DC but also plasmacytoid DC frequencies were significantly reduced in the blood of the cancer patients prior to treatment, as compared to healthy controls. Moreover, besides an accumulated population of immature myeloid cells (ImC), a population of myeloid suppressor cells (MSC) was significantly increased. Upon systemic VEGFR TK inhibition, DC frequencies did not increase, whereas the rate of circulating MSC showed a slight, but not significant, decrease. In conclusion, TK inhibition of VEGFR with AZD2171 does not restore the defective PBDC differentiation observed in advanced cancer patients.

scholarly journals Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3379
Author(s):  
Hannah R. Moorman ◽  
Dakota Poschel ◽  
John D. Klement ◽  
Chunwan Lu ◽  
Priscilla S. Redd ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Cancer ◽  
Macrophage Polarization ◽  
Elevated Serum ◽  
Lymphoid Cells ◽  
Wide Range

OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.

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