Effects of PSK on interleukin-2 production by peripheral lymphocytes of patients with advanced ovarian carcinoma during chemotherapy

The effects of PSK on OKT 4/OKT 8 cell ratio, interleukin-2 (IL-2) production and expression of IL-2 receptor were examined in peripheral blood lymphocytes (PBL) from patients with advanced ovarian cancer during the course of chemotherapy. Preoperative levels of OKT 4/OKT 8 cell ratio and IL-2 production in PBL from patients with advanced ovarian cancer were significantly lower than those in cases of benign ovarian tumor. However, the expression of IL-2 receptor did not show any significant difference between ovarian cancer and benign ovarian tumor patients. When a combination chemotherapy of cisplatin, adriamycin and cyclophosphamide was given, the OKT 4/OKT 8 cell ratio was significantly increased with a significant decrease of the absolute number of the OKT 8 cell subset, while the expression of IL-2 receptor and the absolute number of the OKT 4 cell subset remained unchanged. In contrast, the IL-2 production was markedly depressed after the first course of chemotherapy. When PSK was combined with combination chemotherapy, the degree of inhibition of IL-2 production was reduced (though the effect was not statistically significant). If treatment with PSK was initiated after completion of combination chemotherapy, in addition to a significant elevation of OKT 4/OKT 8 cell ratio the depressed IL-2 production was restored to benign control levels. On the other hand, the expression of IL-2 receptor remained unchanged even if PSK was given after completion of chemotherapy.     

Interleukin-2 activity and the response of peripheral blood lymphocytes in patients with gynecologic malignancies

The interleukin-2 (IL-2) production in peripheral blood lymphocytes (PBL), the response to IL-2, and the IL-2 absorption by PBL was studied in 34 patients with gynecologic malignancies. In addition measurement of the OKT 4/8 cell ratios were made. The OKT 4/8 cell ratio in patients with advanced gynecologic malignancies was significantly lower than that in patients with benign tumor. PBL from advanced cancer patients activated by phytohemagglutinin (PHA) had significantly lower IL-2 productivity than that from patients with benign tumors, while no significant difference was observed in its abilities to respond to IL-2 and to absorb IL-2. The OKT 4/8 cell ratio and IL-2 productivity in PBL of patients with good prognosis were significantly elevated after chemotherapy. On the other hand, PBL of patients with poor prognosis declined to about one-half of the preoperative levels. Although in patients with good prognosis the ability of PBL to respond to IL-2 was not changed before and after treatment, in patients with poor prognosis the response was significantly increased after chemotherapy. However, the ability to absorb IL-2 was not affected by treatment.     

Interleukin 2 activity in peripheral blood mononuclear cells of patients with gynecologic malignancies

We studied production of, absorption of and response to interleukin 2 (IL-2) by peripheral blood mononuclear cells (PBMC) from 66 patients with gynecologic malignancies, in addition to measurement of the OKT 4/OKT 8 cell ratio. Patients with benign tumor served as controls. The OKT 4/OKT 8 cell ratio in patients with advanced (but not early) gynecologic malignancies was significantly lower than that in patients with benign tumor. PBMC from advanced cancer patients activated with phytohemagglutinin (PHA) had significantly lower IL-2 production compared to that from patients with benign tumors, while significant changes in their ability to respond to IL-2 and to absorb IL-2 were not observed. Absolute numbers of OKT 8 positive cells in PBMC of patients with good prognosis were significantly decreased after surgery and chemotherapy, while those of OKT 4 positive cells remained unchanged. Although IL-2 production in PBMC of patients with good prognosis was significantly elevated after chemotherapy, that in PBMC of patients with poor prognosis declined to about a half of pre-operative levels. The ability of PBMC to respond to IL-2 was significantly elevated not only in patients with good prognosis but also in patients with poor prognosis after termination of chemotherapy. On the other hand, the ability of PBMC to absorb IL-2 remained unchanged during the course of treatment. These findings may contribute to the understanding of tumor-induced immune suppression.     

Interleukin 2 activity in peripheral blood mononuclear cells of patients with gynecologic malignancies

We studied production of, absorption of and response to interleukin 2 (IL-2) by peripheral blood mononuclear cells (PBMC) from 66 patients with gynecologic malignancies, in addition to measurement of the OKT 4/OKT 8 cell ratio. Patients with benign tumor served as controls. The OKT 4/OKT 8 cell ratio in patients with advanced (but not early) gynecologic malignancies was significantly lower than that in patients with benign tumor. PBMC from advanced cancer patients activated with phytohemagglutinin (PHA) had significantly lower IL-2 production compared to that from patients with benign tumors, while significant changes in their ability to respond to IL-2 and to absorb IL-2 were not observed. Absolute numbers of OKT 8 positive cells in PBMC of patients with good prognosis were significantly decreased after surgery and chemotherapy, while those of OKT 4 positive cells remained unchanged. Although IL-2 production in PBMC of patients with good prognosis was significantly elevated after chemotherapy, that in PBMC of patients with poor prognosis declined to about a half of pre-operative levels. The ability of PBMC to respond to IL-2 was significantly elevated not only in patients with good prognosis but also in patients with poor prognosis after termination of chemotherapy. On the other hand, the ability of PBMC to absorb IL-2 remained unchanged during the course of treatment. These findings may contribute to the understanding of tumor-induced immune suppression.     

Immunoregulatory T-lymphocyte functions in patients with small cell lung cancer

The present study was performed to elucidate the differences in immune status between patients with small cell lung cancer (SCLC) and those with non-small cell lung cancer. The study group consisted of 18 patients with SCLC and 15 with non-SCLC. Two healthy volunteers and 13 patients with benign disease were also included in the present study as the non-cancer control. In the non-SCLC group, although not statistically significant, the percentages of both OKT3+ and OKT4+ T-lymphocytes in the peripheral blood lymphocytes (PBL) were slightly decreased, associated with a slight increase in the percentage of OKT8+ T-cells, and a slight decrease in the OKT4+ to OKT8+ T-cell ratio. In contrast, the PBL of the SCLC patients showed significantly lower proliferative responses to phytohemagglutinin and human recombinant interleukin 2 than did the PBL of both the SCLC patients and the noncancer control group. The ability of PBL to produce lymphokines (interleukin 2 and macrophage activating factor) was significantly impaired in the SCLC group but not in the non-SCLC group. These results suggest that suppression of helper T-cell functions and/or potentiation of suppressor T-cell functions should occur in patients with SCLC.     

Elevation of interleukin-2 production in peripheral-blood lymphocytes by recombinant human granulocyte-colony-stimulating factor in ovarian-cancer patients during combination chemotherapy

Interleukin-2 (IL-2) production and peripheral blood lymphocyte (PBL) subsets were measured in ovarian cancer patients who received cis-platinum based chemotherapy with or without recombinant human granulocyte colony stimulating factor (rhG-CSF). Additional treatment with rhC-CSF resulted in significant elevation of IL-2 production and highly differentiated natural killer (NK) cell counts, indicating that rhG-CSF may be helpful for enhancement of the cellular immunity in ovarian cancer patients.     

云芝多糖对肿瘤患者免疫功能的影响

本文对45例服用云芝多糖的恶性肿瘤患者,于服药前后,用间接免疫荧光法,检测了这些患者外周血中的T淋巴细胞亚群:T3,T4,T8细胞数;T4/T8比值、Tac(IL_2受体),和B淋巴细胞数。其中部分患者做了末稍血白细胞、血小板计数,血红蛋白测定及白细胞分类。服用云芝多糖后,T_3、T_4淋巴细胞亚群及白细胞计数均较服药前显著增高(P<0.05),余无显著变化(P>0.05)。本文认为云芝多糖是一较好的生物反应调节剂。可做为肿瘤治疗的辅助性药物。     

Effects of antiestrogen and progestin on immune functions in breast cancer patients

Several immunologic variables were evaluated in 14 patients with untreated primary breast cancer and 20 postmastectomized patients undergoing tamoxifen (TAM) or high-dose medroxyprogesterone acetate (MPA) treatment. Immunologic evaluation in the peripheral blood included lymphocyte count, definition of T-lymphocyte subsets by monoclonal antibodies (OKT3, OKT11, OKT4, and OKT8), and lymphocyte blastogenic response to phytohemagglutinin (PHA) and Concanavalin A (Con A). Moreover, the in vitro effect of TAM and MPA on the blastogenic response of peripheral lymphocytes from normal female subjects was tested. Primary breast cancer patients did not differ from controls in any of the variables tested. Similarly, the immunologic variables of the group treated with TAM were normal, with the exception of a slight reduction of the OKT4+/OKT8+ ratio. In MPA-treated patients, a reduction of the percentage of OKT4+ cells and a decrease of the OKT4+/OKT8+ ratio were observed. Moreover, response to PHA was reduced sharply. However, the addition of interleukin-2 (IL-2) to the culture medium restored PHA response. Likewise, the in vitro addition of MPA to peripheral blood lymphocytes from normal female subjects resulted in a sharp dose-dependent depression of PHA response while TAM was ineffective completely. The inhibitory effect of MPA was not evident when IL-2 was added simultaneously to the culture medium. These results show that the administration of high-dose MPA may alter immunocompetence as defined by T-lymphocyte subsets and response to mitogens. The latter effect may be related to a diminished production of IL-2. In contrast, TAM does not appear to have a significant immunodepressant action either in vitro or in vivo.     

卵巢恶性肿瘤患者细胞免疫状免疫状态的研究及临床价值：COKT McAb...

Blood samples from 79 subjects (27 cases of ovarian malignancy, 2 ovarian borderline epithelial tumor, 38 benign gynecologic disease and 12 healthy women) were measured for peripheral blood T-cell subsets using monoclonal antibodies and SPA-Ig rosette technique. It was found that in patients with ovarian malignancy, the percentage of OKT4+ cells was significantly reduced whereas the percentage of OKT8+ cells was markedly increased as compared with those in the healthy women and patients with benign gynecologic disease; OKT4/OKT8 ratio declined obviously; which were more pronounced in patients with advanced or recurrent tumor.     

Relationships of Ex-Vivo Drug Resistance Assay and Cytokine Production with Clinicopathological Features in the Primary Cell Culture of Thai Ovarian and Fallopian Tube Cancer Patients

Objective: Our goal was to determine the ex-vivo drug resistance assay, as well as the cytokine production, in response to platinum-based chemotherapy treatment in primary culture cells established from the tumor tissue of ovarian or fallopian tube carcinoma patients, and to predict the clinical responses to chemotherapy. Methods: Sensitivity to the platinum-based drug was analyzed in two ovarian cancer cell lines and 19 tumor samples using the primary cell culture obtained from 19 patients having ovarian or fallopian tube cancer that had undergone surgery from 2014 to 2017. Results: Our findings in the ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production. Regarding the primary cell culture obtained from patients, ex-vivo drug resistance assay results revealed that although extreme drug resistance was correlated with late stage ovarian cancer (P= 0.031), it could not independently predict or alter the outcomes of patients with ovarian or fallopian tube cancer. No relationship was found between basal cytokine secretion and the clinical parameters. However, carboplatin-induced IL-6 and IL-8 production had a significant association with the clinical response to chemotherapy (P=0.016 and P=0.038 respectively). Carboplatin-induced IL-8 overproduction was correlated with FIGO staging III-IV (P=0.026), but no correlation between carboplatin-induced IL-6 and FIGO staging (P= 0.061) was noted. Conclusion: These results suggest that cytokine production in response to platinum-based chemotherapy in primary culture cells may be useful as a predictive marker for the therapeutic outcomes among ovarian or fallopian tube cancer patients.     

Evidence for HTLV-III/LAV expression by primary cultures of T8 cells

The selective targets for HTLV-III/LAV, the causal infectious agent of AIDS and AIDS-related complex (ARC), are T4 cells, apparently because the virus receptor is associated with T4 antigen determinants. This accounts for T4 cell depletion in AIDS and for a decrease of IL-2 production by AIDS peripheral blood lymphocytes (PBL) after in vitro PHA activation. By contrast, T8 cells are not targets for HTLV-III/LAV, since T8 cells from PBL and from long-term cultured T cells (CTC) could not be infected by the virus. We describe 2 samples of PBL from Zairian patients with HTLV-III infection in which HTLV-III was expressed by T8 cells. Evidence that T8 cells were expressing virus was obtained by complement cytotoxicity experiments performed in the presence of OKT8 monoclonal antibody (MAb), which removed HTLV-III-positive cells from cultured T cells producing the virus, and by double labelling experiments, in which some cells exhibit both T8 antigens detected either by IFA (rhodamine) or by rosetting in presence of OKT8 MAbs and HTLV-III antigens detected by IFA (fluorescein) with of anti-HTLV-III p24 and p15 MAbs. Since normal T cells have previously been shown to undergo antigenic diversity, we think these results can be explained by HTLV-III infection of T4 cells which later lost T4 antigens and acquired the T8 phenotype.     

卵巢肿瘤组织中的P—糖蛋白表达及其临床意义探讨

采用免疫组织化学法对５３例卵巢恶性肿瘤，２０例卵巢良性肿瘤和１７例正常卵巢组织进行Ｐ－糖蛋白表达测定。同时，进行相关临床因素分析。结果显示：１）卵巢恶性肿瘤组织中Ｐ－糖蛋白表达阳性率为３５．８％，而卵巢良性肿瘤和下沉卵巢组织中则无１例Ｐ－糖蛋白表达阳性。２）在卵巢恶性肿瘤中，初治者和复发者的Ｐ－糖蛋白表达阳性率分别为２７．８％和５２．８％。３）Ｐ－糖蛋白表达阳性和阴性的卵巢恶性肿瘤患者，对化疗的有     

Role of the IL-33/ST2 receptor axis in ovarian cancer progression

Ovarian cancer remains a significant health problem for women in the world due to its diagnosis at advanced stages of disease and the high mortality rate of patients. To date, ovarian cancer is frequently treated with tumor reduction surgery followed by platinum/paclitaxel-based chemotherapy; however, most patients eventually develop relapsed disease. The mRNA expression levels of interleukin-33 (IL-33) and the suppressor of tumorigenicity 2 (ST2) receptor are significantly upregulated in ovarian cancer tissues and metastatic tumor lesions. In addition, IL-33 and ST2 expression has been associated with a poor overall survival in patients with epithelial ovarian cancer. The IL-33 receptor ST2 is expressed as both a membrane-anchored receptor (ST2L) activated by IL-33, and as a soluble variant that exhibits anti-inflammatory properties. In the present review, the functions of the IL-33/ST2L axis in cells and their aberrant expression levels in ovarian cancer were discussed. In addition, targeting their expression as a novel strategy for the control of ovarian cancer progression was emphasized.     

Lysis of Fresh Human Tumor Cells by Autologous Peripheral Blood Lymphocytes and Tumor-infiltrating Lymphocytes Activated hy PSK

The protein-bound polysaccharide PSK was tested for the ability to induce in vitro autologous tumor killing (ATK) activity in human cancer patients. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) demonstrated various levels of cytotoxicity against autologous, freshly isolated tumor cells. When PBL and TIL were cultured overnight with PSK, ATK activity was induced in previously non-reactive cases and augmented in previously reactive samples. The PSK effect was observed with PSK concentrations of 10–100 μg/ml that could be obtained in the blood of cancer patients who received standard oral administration of PSK. The manifestation of PSK-induced ATK required active cell metabolism and RNA and protein syntheses, but not DNA synthesis of lymphocytes. PSK-induced enhancement of ATK was not abrogated by monoclonal antibodies (mAb) directed against interferon (IFN)α or IFNγ-. In addition, mAb that neutralized interleukin-2 (IL-2) or mAb reactive with α-chain or β -chain of IL-2 receptors (IL-2R) had no effect on PSK-induced ATK activity. Supernatants from PSK-stimulated lymphocyte cultures did not induce ATK. Cell fractiona-tion experiments revealed that CD3^-CD16⁺ large granular lymphocytes (LGL) and/or CD3⁺CD16^- T lymphocytes were responsible for both spontaneous and PSK-induced ATK. PSK-activated LGL, but not T lymphocytes expressed lysis of fresh allogeneic tumor cells. These results indicate that PSK activates PBL and TIL to exhibit ATK independently of IL-2/IL-2R systems.     

T-Lymphocyte Subsets in Primary Lung Cancer

T-cell subsets in the peripheral blood of 63 primary lung cancerpatients (23 with adenocarcinoma, 23 with squamous cell carcinomaand 17 with small cell carcinoma) and 24 normal healthy controlswere determined by indirect im-munofluorescence, using the monoclonalantibody reagents OKT3, OKT4 and OKT8. Correlations betweenT-lymphocyte subset values and stages or cell types of diseasewere sought. Total lymphocytes in the patient group were decreased.However, no significant difference from controls was seen inthe percentage of OKT3-positive cells (Pan T-cells) in the cancerpatients. The percentage of OKT8-positive cells (cytotoxic/suppressor)was increased in the early stage of disease whereas the percentageof OKT4 positive cells (inducer/helper) remained at the controllevel throughout all stages. The ratio of OKT4-positive to OKT8-positiveT-cells (OKT4/OKT8), reflecting the balance of immunoregula-toryT-cells, was, therefore, significantly decreased in patientswith stage I–II lung cancer (P < 0.05), especiallyin squamous cell lung cancer (P < 0.05), whereas in stagesIII or IV, this T4/T8 ratio returned to the control level. Insmall cell carcinoma, the T4/T8 ratio was significantly decreasedin stage III (P < 0.01) and returned to the control levelin stage IV.     

Lysis of fresh human tumor cells by autologous peripheral blood lymphocytes and tumor-infiltrating lymphocytes activated by PSK

The protein-bound polysaccharide PSK was tested for the ability to induce in vitro autologous tumor killing (ATK) activity in human cancer patients. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) demonstrated various levels of cytotoxicity against autologous, freshly isolated tumor cells. When PBL and TIL were cultured overnight with PSK, ATK activity was induced in previously non-reactive cases and augmented in previously reactive samples. The PSK effect was observed with PSK concentrations of 10-100 micrograms/ml that could be obtained in the blood of cancer patients who received standard oral administration of PSK. The manifestation of PSK-induced ATK required active cell metabolism and RNA and protein syntheses, but not DNA synthesis of lymphocytes. PSK-induced enhancement of ATK was not abrogated by monoclonal antibodies (mAb) directed against interferon (IFN) alpha or IFN gamma. In addition, mAb that neutralized interleukin-2 (IL-2) or mAb reactive with alpha-chain or beta-chain of IL-2 receptors (IL-2R) had no effect on PSK-induced ATK activity. Supernatants from PSK-stimulated lymphocyte cultures did not induce ATK. Cell fractionation experiments revealed that CD3-CD16+ large granular lymphocytes (LGL) and/or CD3+CD16- T lymphocytes were responsible for both spontaneous and PSK-induced ATK. PSK-activated LGL, but not T lymphocytes expressed lysis of fresh allogeneic tumor cells. These results indicate that PSK activates PBL and TIL to exhibit ATK independently of IL-2/IL-2R systems.     

β-淀粉样蛋白在卵巢癌组织中的表达及与临床关系研究

目的 研究β-淀粉样蛋白(Amyloid beta A4 protein,APP)mRNA在卵巢肿瘤患者组织中的表达,并探讨其临床意义.方法 Trizol一步法提取卵巢肿瘤患者卵巢组织总RNA,实时荧光定量PCR技术对49例卵巢癌、20例卵巢良性肿瘤、16例正常卵巢组织进行定量分析.结果 APP mRNA在卵巢癌中表达量比在卵巢良性肿瘤和正常卵巢组织中明显升高(P＜0.05);卵巢颗粒细胞瘤患者组织APP的表达显著高于上皮性卵巢癌(P＜0.05);术前行新辅助化疗的卵巢癌患者APP表达量显著高于良性组和正常对照组,但与非化疗患者的表达没有差异,提示化疗不会降低其表达量.APP表达量与卵巢癌患者的生存率无显著相关性,不是独立判断卵巢恶性肿瘤患者预后的因素.结论 卵巢癌患者肿瘤组织APP mRNA水平显著高于良性和正常对照组,并在卵巢颗粒细胞瘤中高表达,提示其增高与恶性肿瘤的组织学类型有关,具有一定的临床诊断意义和价值.     

The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma

Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.     

Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer

Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8(+) cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8(+) T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccessful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8(+) T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8(+) T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-gamma expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8(+) T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8(+) CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.