IL-17 and VEGF are increased and correlated to systemic inflammation, immune suppression, and malnutrition in patients with breast cancer

Relationships between inflammation and innate immunity in cancer are widely accepted today; however, the precise cell mechanisms mediating these relationships have not yet been elucidated. Interleukin (IL)-17 is a proinflammatory cytokine that has been reported to induce inflammation in patients with autoimmune diseases. Myeloid-derived suppressor cells (MDSC) may contribute to the negative regulation of immune responses during cancer and inflammation. Vascular endothelial growth factor (VEGF) is reported to have multiple biological actions including increasing vascular permeability, neovascularization, and possible inhibition of immune function in malignant diseases. This study investigated the status of systemic inflammation and immune suppression associated with IL-17 and VEGF in patients with breast cancer. IL-17 production and the serum levels of VEGF were also increased in advanced stages of the disease. The production of IL-12, which induces Th1 cells, and the stimulation index (SI), which is a marker of cell-mediated immune function, were both shown to decrease along with disease advancement. Also, the production of IL-17 and the VEGF levels were both positively correlated with the levels of MDSC, the neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and were inversely correlated with IL-12 production and the SI. Nutritional markers, including prealbumin (PA), transferrin (TF), and retinol-binding protein (RBP), were also shown to be significantly lower in patients with high production of IL-17 or high levels of VEGF. These data clearly showed that IL-17 and VEGF, whose levels correlated with each other and with those of MDSC, were significantly associated with disease advancement, systemic inflammation, suppression of cell-mediated immunity including Th1 induction, and malnutrition.

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Correlation of VEGF with immune suppression involving MDSC, malnutrition, and prognosis in patients with gastric and colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.582 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 582-582 ◽

Cited By ~ 1

Author(s):

Kenji Gonda ◽

Masahiko Shibata ◽

Daisuke Ujiie ◽

Mai Ashizawa ◽

Hirokazu Okayama ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Suppression ◽

Stimulation Index ◽

Suppressor Cells ◽

Serum Levels ◽

Retinol Binding Protein ◽

Vascular Permeability Factor ◽

Reactive Protein ◽

Cell Mediated Immune Response ◽

Immunosuppressive Cells

582 Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Vascular endothelial growth factor (VEGF), previously known as vascular permeability factor. 45 kDa protein, belongs to a family of platelet-derived growth factors. VEGF, inflammation-related protein, could contribute to the accumulation of immunosuppressive cells (MDSC, Treg, TAM, and Tie-2-expressingmonocytes) in tumor-bearing hosts through direct or indirect mechanisms. Methods: We tested the serum levels of VEGF by ELISA in 106 patients including 43 with gastric and 63 with colorectal cancer, and they were increased in advanced stages of gastric and colorectal cancer. Production of IL-17, pro-inflammatory cytokine, with a stimulation of PHA was measured by ELISA and MDSC (myeloid-derived suppressor cells), one of major immunosuppressing cells, was measured by flow cytometry (CD11b+CD14-CD33+). Neutrophil to lymphocyte ratio (NLR) and C-reactive protein (CRP) were used as inflammatory markers. Production of IL-12 and SI (stimulation index) of blastogenic response of lymphocytes were used as markers of cell-mediated immune response. Results: The concentrations of VEGF were positively correlated with levels of MDSC, production of IL-17, NLR and CRP, and were inversely correlated with IL-12 production, SI and nutritional markers including prealbumin and retinol binding protein. The patients were both divided into two groups with a serum level of VEGF (330 pg/ml) and OS (overall survival) of patients with stages III and IV gastric or colorectal cancer were both significantly worse in patients with high levels of VEGF than in those with low VEGF although the differences were not significant in patients with stagesⅠand II. Conclusions: The results of the present study suggested that VEGF may have an impact on advancement and progression involving inflammation and serve as useful markers of the immune suppression involving MDSC, malnutrition and poor prognosis in patients with gastric and colorectal cancer.

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Correlation of IL-17 with immune suppression involving MDSC, malnutrition, and prognosis in patients with gastric and colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.83 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 83-83 ◽

Cited By ~ 1

Author(s):

Kenji Gonda ◽

Masahiko Shibata ◽

Daisuke Ujiie ◽

Mai Ashizawa ◽

Tomohiro Kikuchi ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Suppression ◽

Stimulation Index ◽

Suppressor Cells ◽

Retinol Binding Protein ◽

Reactive Protein ◽

Th 17 ◽

Cell Mediated Immune Response ◽

Inflammatory Processes ◽

Advanced Stages

83 Background: Although a causal relationship linking inflammation and cancer immunity is more widely accepted today, precise cell mechanisms mediating this relationship have not been elucidated. IL-17, a pro-inflammatory cytokine primarily secreted by T helper (Th)17 cells, has previously been associated with inflammatory processes in autoimmune disease. The presence of IL-17 and Th17 cells has been confirmed in various invasive cancers and recently linked to immunosuppression in cancer patients. We investigated systemic inflammation, immune suppression, malnutrition, and prognosis associated with IL-17 in patients with gastric and colorectal cancer. Methods: We measured IL-17 in 106 patients, including 43 with gastric and 63 with colorectal cancer, Production of IL-17 stimulated by PHA was measured by ELISA. MDSC (myeloid-derived suppressor cells), which significantly contribute to immunosuppression, were measured by flow cytometry (CD11b+CD14-CD33+). Neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were used as inflammatory markers. Production of IL-12 and the SI (stimulation index) of lymphocytes’ blastogenic response were used as markers of cell-mediated immune response. Results: Production of IL-17 increased in advanced stages of gastric and colorectal cancer. IL-17 positively correlated with levels of MDSC, serum concentrations of VEGF, NLR, and levels of CRP, and was inversely correlated with IL-12 production, SI, and nutritional markers including prealbumin and retinol binding protein. Patient cohorts were divided into two groups with IL-17 level (540 pg/ml) and OS (overall survival) of patients with stages III and IV gastric or colorectal cancer both significantly worse in patients with high production of IL-17 than in those with low IL-17, although the differences were not significant in patients at stages I and II. Conclusions: The present study suggests that IL-17 may reflect an inflammatory impact on the advancement and progression of cancer, and it may serve as useful marker of immune suppression involving MDSC, malnutrition, and poor prognosis in patients with gastric and colorectal cancer.

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Pretreatment serum levels of myeloid-derived suppressor cells (MDSC) are effective as a prognostic indicator in patients with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.e14006 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. e14006-e14006 ◽

Cited By ~ 1

Author(s):

Kenji Gonda ◽

Masahiko Shibata ◽

Takahiro Nakajima ◽

Yoshiko Matsumoto ◽

Noriko Abe ◽

...

Keyword(s):

Breast Cancer ◽

Suppressor Cells ◽

Serum Levels ◽

Prognostic Indicator ◽

Myeloid Derived Suppressor Cells ◽

Pretreatment Serum

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Serum levels of vascular endothelial growth factor in patients with gastrointestinal cancers and correlation with malnutrition, immunosuppression involving MDSC, and systemic inflammation.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.514 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 514-514

Author(s):

Kenji Gonda ◽

Masahiko Shibata ◽

Satoshi Suzuki ◽

Izumi Nakamura ◽

Kensuke Kumamoto ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Healthy Volunteers ◽

Systemic Inflammation ◽

Lymphocyte Count ◽

Serum Levels ◽

Retinol Binding Protein ◽

Vascular Endothelial ◽

Serum Concentrations ◽

Endothelial Growth Factor

514 Background: Vascular endothelial growth factor (VEGF) reportedly plays an important role in the progression of malignant neoplasms, and have been reported to induce myeloid-derived suppressor cells (MDSC) that appears in cancer and inflammation. Methods: Blood samples were collected from 57 patients, including 8 with esophageal cancer, 20 with gastric cancer, 29 with colorectal cancer, and from 18 healthy volunteers. We measured serum concentrations of VEGF and analyzed correlations with nutritional damage, immune suppression and systemic inflammation. As markers of immune function, IL-12 production of PBMC and MDSC (CD 11b+, CD14-, CD33+) were measured. Serum concentrations of albumin and rapid turnover protein were measured as a marker of nutritional status. Results: A significant increase in serum levels was seen in patients with esophageal, gastric, and colorectal cancers compared to healthy volunteers. Levels of VEGF were inversely correlated with serum concentrations of albumin, prealbumin and retinol-binding protein. Serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)-12 and correlated with MDSC. VEGF levels also correlated with neutrophil count and neutrophil/lymphocyte count, and correlated inversely with lymphocyte count. Serum VEGF levels were then divided about a cutoff of 500 pg/ml, with levels of prealbumin and retinol-binding protein significantly decreased in patients with higher VEGF levels. Stimulation index and IL-12 production were significantly decreased in the group with higher VEGF levels, and MDSC counts tended to be higher in this group. Conclusions: These results demonstrated that increased production of VEGF correlated with systemic inflammation, nutritional impairment and inhibition of cell-mediated immunity involving MDSCs. An inactivation of dendritic cells may be occurring by the activation of MDSC. Anti-VEGF therapy may be of importance in treating digestive system cancers.

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The Effects of Press Needle on Immune Function and Quality of Life Among Female Breast Cancer Patients After Radical Mastectomy: Study Protocol for a Randomised Controlled Trial

10.21203/rs.3.rs-757641/v1 ◽

2021 ◽

Author(s):

Ying Gao ◽

Yao Wang ◽

Hongchu Chen ◽

Ran Yan ◽

Tao Liu ◽

...

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Immune Function ◽

Cancer Patients ◽

Immune Suppression ◽

Radical Mastectomy ◽

Female Breast Cancer ◽

Breast Cancer Patients ◽

Female Breast

Abstract BackgroundRadical mastectomy may lead to suppression of cellular immune function in patients with malignant tumors, and affect the quality of life (QOL) of patients. Immune suppression is a common cause of complications and adverse reactions in adjuvant therapy after radical mastectomy of breast cancer. Currently, there are few proven effective treatments for immune suppression. Therefore, it’s necessary to develop a new treatment method. Press needle is widely used in clinical practice. However, there have been relatively few studies that evaluate the effects of press needle on postoperative immune function. The aim of the present study is to assess the effects of press needle on immune function and QOL in female breast cancer patients undergoing radical mastectomy.MethodsThis study will be a single-center, randomized and single-blinded trial. 78 eligible patients will be randomized in a ratio of 1:1 to the press needle group or the sham press needle group. During the treatment phase, patients will undergo five times weekly of verum press needle or sham press needle for 2 weeks, and then they will be followed-up for 2 weeks. The primary outcome measures will be the peripheral blood levels of CD8+, CD4+, CD3+, and CD4+/CD8+ T cells. The secondary outcome measures will be the changes of patients’ QOL, evaluated by the Karnofsky Performance Scale (KPS) score and the EORTC core quality of life questionnaire (EORTC QLQ-C30). Safety and adverse events will be assessed at each visit. DiscussionThe results of this on-going study will provide clinical evidence for the effects and safety of press needle on immune function and QOL in patients after breast cancer resection compared with sham press needle.Trial registrationChinese Clinical Trial Registry, ChiCTR2000040100. Registered on 21 November 2020.

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Elevated Serum Levels of Retinol-Binding Protein 4 Are Associated with Breast Cancer Risk: A Case-Control Study

PLoS ONE ◽

10.1371/journal.pone.0167498 ◽

2016 ◽

Vol 11 (12) ◽

pp. e0167498 ◽

Cited By ~ 8

Author(s):

Congcong Jiao ◽

Lianhua Cui ◽

Aiguo Ma ◽

Na Li ◽

Hongzong Si

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Case Control Study ◽

Elevated Serum ◽

Serum Levels ◽

Case Control ◽

Retinol Binding Protein ◽

Retinol Binding Protein 4 ◽

Control Study

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Does obesity change the effect of aromatase inhibitors (AIs) on estradiol, leptin, insulin, and IGF-1 serum levels in breast cancer patients?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11008 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11008-e11008

Author(s):

Mehmet Artac ◽

Dudu Askin ◽

Aysel Kiyici ◽

Onder Orhan Eren ◽

Mufide Oncel ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Postmenopausal Breast Cancer ◽

Serum Levels ◽

Breast Cancer Patients ◽

Related Factors ◽

The Status ◽

The Relationship ◽

Estradiol Levels

e11008 Background: The complexity of the relationship between obesity and breast cancer reflects important contributions of obesity-related factors in the adjuvant therapy. The efficacy of adjuvant AIs compared to tamoxifen is lower in obese postmenopausal women. Therefore, we aimed to identify whether the effect of AIs on estradiol, leptin, insulin, and IGF-1 serum levels with respect to the status of the obesity in breast cancer patients. Methods: A total of 34 postmenopausal breast cancer patients treated with adjuvant AIs were enrolled in the study. Pretreatment and 3 months after treatment body weight, height, waist-to-hip (WHR) ratio and body mass index (BMI) were recorded. Blood samples for serum estradiol, leptin, insulin and IGF-1 were drawn after 12 hour starvation and stored in – 70o before and 3 months after the onset of AI treatment. Results: Median age and BMI were 61 years (range 49-84) and 31 (range 22-43), respectively. 18 (%52.9) patients were treated with letrozole and 16 (%47.1) patients were treated with anastrazole. There was no change in the 3 months period in weight, BMI and WHR. Estradiol levels were decreased significantly between the baseline and the 3rd month (p<0.01). There was a slight increase in the leptin levels between the basal and 3rd month (p>0.05). No significant change was detected in insulin and IGF-1 levels in the follow-up period. In the multivariate regression model, there was no difference between the effect of letrozole and anastrazole on estradiol levels. Pretreatment BMI did not alter the effect of AIs on estradiol levels. The only factor related with the effect of the AIs is the pretreatment estradiol levels. Conclusions: This study shows that the suppression of estrogen in obese breast cancer patients with AIs at the standard doses may not be different from non-obese patients. Further researches may show us other mechanisms for the obesity-related factors to improve outcome with aromatase inhibition in obese breast cancer patients.

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Multiple immunological mechanisms of cancer cachexia in patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.667 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 667-667

Author(s):

Kenji Gonda ◽

Masahiko Shibata ◽

Izumi Nakamura ◽

Shinji Ohki ◽

Koji Kono ◽

...

Keyword(s):

Immune Function ◽

Chronic Inflammation ◽

Cancer Cachexia ◽

Mononuclear Cells ◽

Retinol Binding Protein ◽

Cell Mediated Immunity ◽

Serum Concentrations ◽

Peripheral Blood Mononuclear ◽

Neutrophil Lymphocyte Ratio ◽

Immunological Mechanisms

667 Background: Cancer cachexia is a mixed and multiple factorial condition and commonly seen in patients with advanced cancer, and has long been reported that host-immune function is critically participated. Chronic inflammation plays a key role in the progress of malignant diseases and has been reported to relate with immune suppression and nutritional impairment seen in patients with advanced diseases. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers and 112 patients with gastrointestinal cancer. These cells were used for the detection of MDSC (myeloid-derived suppressor cells: 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) and for the production assay of cytokines including IFN-G, IL-6 and IL-10. Serum levels of soluble cytokine receptors including sIL-2R and sTNF-R1, and anti-inflammatory molecules such as IL-10 and IL-1 receptor antagonist (IL-1RA) were also measured. For the evaluation of nutritional status, serum concentrations of rapid turnover protein (RTP) including prealbumin, transferrin and retinol binding protein was measured. NLR (neutrophil/lymphocyte ratio) was calculated and used as a marker of chronic inflammation. Results: The circulating levels of MDSC was significantly increased in esophageal, gastric and colorectal carcinomas than in normal volunteer and significantly inversely correlated with serum concentration of RTP and with SI, and correlated with markers for inflammation. The levels of sIL-2R and sTNF-R1 were increased in patients with gastric and colorectal and inversely correlated with the levels of RTP and SI. In patients with cachexia, serum concentrations of IL-10 were increased and the production of IFN-G was decreased. Conclusions: It is suggested that suppression of cell-mediated immune function exists in patients with cancer cachexia and the immunological mechanisms of nutritional damages in these patients are even partially driven by Th2-dominant condition of CD4(+) cells and MDSC. These complicated mechanisms are also involved in inflammation-related immunological condition such as SIRS and CARS.

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