Immune Status and Immune Therapy of Renal Cell Carcinoma

Bichler, K.-H.; Kleinknecht, S; Strohmaier, Walter

doi:10.1159/000281720

Cited by 18 publications

(9 citation statements)

References 27 publications

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“…There are very few studies on serum TNFa and IL-1b in RCC patients. Bichler et al (1990) reported that when serum TNFa level was measured in 29 RCC patients, patients with metastatic disease could exhibit increased levels of serum TNF and that the decrease in TNF may be associated with a better prognosis. Dosquet et al (1997) reported that plasma TNFa level was higher in RCC patients compared to healthy controls, and that it was higher in the disseminated group compared to the undisseminated group.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6, tumour necrosis factor α and interleukin-1β in patients with renal cell carcinoma

et al. 2002

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As regulators of malignant cell behaviour and communication with stroma, cytokines have proved useful in understanding cancer biology and developing novel therapies. In renal cell carcinoma, patients with inflammatory reactions are known to have poor prognosis. In order to elucidate the relation between renal cell carcinoma and the host, serum levels of inflammatory cytokines, interleukin-6, tumour necrosis factor a, interleukin-1b, were measured. One hundred and twenty-two patients with renal cell carcinoma and 21 healthy control subjects were studied, and serum cytokine levels were measured using a highly sensitive ELISA kit. As a result, in the control group, interleukin-6, tumour necrosis factor a and interleukin-1b levels were 1.79+2.03, 2.74+0.94 and 0.16+0.17 pg ml 71, respectively. In the renal cell carcinoma patients, they were 8.91+13.12, 8.44+4.15 and 0.53+0.57 pg ml 71 , respectively, and significantly higher. In the comparison of stage, interleukin-6 level was significantly higher in the stage IV group compared to the other stage groups including the control group, while tumour necrosis factor a level was significantly higher in each stage group compared to the control group. As for grade, interleukin-6 level was significantly higher in the grade 3 group compared to the control, grade 1 and grade 2 groups, while tumour necrosis factor a level was significantly higher in each grade group compared to the control group. All cytokines had a positive correlation with tumour size. In regard to the correlation with CRP, all cytokines had a positive correlation with CRP, while interleukin-6 had a particularly strong correlation. In conclusion, interleukin-6 may be one of the factors for the poor prognosis of patients with renal cell carcinoma. In addition, tumour necrosis factor a may be useful in the early diagnosis of renal cell carcinoma and post-operative follow-up.

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Section: Discussionmentioning

confidence: 99%

Interleukin-6, tumour necrosis factor α and interleukin-1β in patients with renal cell carcinoma

et al. 2002

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“…Although RCC is infiltrated by numerous T cells, confirming that the immune system may control the growth of these tumors, this tumor model is also characterized by the existence of various immune defects that result in the global functional alteration of the cytotoxic T-effector cells. [32][33][34] It is known that human solid tumors mostly express tissue-specific antigens or self-antigens that may induce local tolerance, and cytotoxic T cells infiltrating RCC may correspond to antigenexperienced CTLs. In accordance with this hypothesis, we have previously shown that clonal KIR ϩ CTLs, bearing a memoryactivated phenotype, infiltrated RCC.…”

Section: Discussionmentioning

confidence: 99%

Engagement of the inhibitory receptor CD158a interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction

Guerra

Michel

Gati

et al. 2002

Blood

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IntroductionIn humans, inhibitory natural killer (NK) receptors for HLA-I molecules include killer cell immunoglobulinlike receptors (KIRs), the CD94/NKG2A heterodimer, and immunoglobulinlike transcript 2 (ILT-2)/leukocyte immunoglobulinlike receptor 1 (LIR-1). Although KIRs recognize specific polymorphisms on the classical HLA-A, -B, and -C molecules, CD94/NKG2A recognizes nonclassical HLA-E molecules assembled with a peptide from the leader sequence of HLA-I molecules. 1,2 ILT-2/LIR-1 expressed by NK, T, and myeloid cells recognizes a broad range of cellular HLA-I molecules 3 as well as viral class I-like molecule, UL-18. 4 All these inhibitory receptors have in common one or more immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic tails. On tyrosine phosphorylation, ITIMs recruit tyrosine phosphatases Src homology 2 domain-containing protein 1 (SHP-1) and/or SHP-2 that can dephosphorylate molecules involved in immunotyrosine-based activation motif (ITAM)-induced signaling pathways. 5,6 KIR2D CD158 receptors possessing 2 immunoglobulin domains are recognized by specific monoclonal antibodies (mAbs) and distinguish HLA-C alleles. 7 In the peripheral blood of healthy individuals, low percentages of KIR ϩ T cells express a memory CD28 Ϫ , CD45RA Ϫ , CD45RO ϩ phenotype and a restricted T-cell receptor (TCR) repertoire. 8,9 These cells may expand in response to chronic antigenic stimulation to self-antigen and most likely represent a precise subset of the memory T-cell pool. 10,11 It has been reported that inhibitory NK receptors expressed by CD8 ϩ cells were able to counterbalance TCR-mediated activation by inhibitory signals that are transduced on specific binding to HLA-I molecules. 8,12,13 A few studies have reported that CD94 and KIRs are also expressed by CD8 ϩ T cells infiltrating tumors. [14][15][16] We previously reported that renal tumors contained particular CD8 ϩ infiltrating T cells that express an inhibitory NK receptor from the KIR family (CD158), specific for HLA-C molecules. In vitro, these KIR ϩ cytotoxic T lymphocytes (CTLs) correspond to potential highly lytic effectors, but their functional activity toward tumor cells is strongly inhibited by the NK receptor. 17 In the present study, a tumor-derived CD158a ϩ CTL was stimulated by tumor cells expressing or not the KIR ligand to investigate the influence of the KIR engagement in the early biochemical and morphologic events leading to cell activation. This system constitutes an accurate model to analyze the interplay between TCR/major histocompatibility complex (MHC) and KIR/MHC interactions during physiologic CTL/target activation.The recognition of MHC/peptide complex by TCRs results in the activation of protein tyrosine kinases (PTKs). 18 Among them, ZAP-70 phosphorylates the adaptor molecule linker for activation of T cells (LAT) that plays a key role in linking TCRs to phospholipase C␥1 and Ras pathways. 19 LAT is also implicated in actin cytoskeleton remodeling required for the TCR-induced membrane spreading. 20 TCR-...

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“…As described in more detail previously [6], leukocyte counts and differential blood counts (Technicon H I, Bayer Diagnostics, München, FRG) as well as lym phocyte subsets were assayed immediately after the blood samples had been taken. PBMC were harvested on Ficoll-Paque density gra dient (Pharmacia.…”

Section: Immunomonitoringmentioning

confidence: 99%

“…immunomonitoring must be regarded as an essential component of immunotherapy which allows optimization of therapy schedules by giving insight into the patients' individual immune system and the effect of immunotherapy. By means of monitoring cellular and humoral immune pa rameters of the peripheral blood during unspecific immunostimulalion in patients with metastatic RCC, we had found evidence of immunosuppression, which may im pair the immunostimulating effects of immunotherapy [6][7][8][9]. Immunosuppression in tumor patients can be me diated through different pathways ( fig.…”

Section: Introductionmentioning

confidence: 99%

Influence of Immunotherapy (IL2 + LAK + Inhibition of Prostaglandin Synthesis) on Peripheral Blood Immune Parameters and in vitro Cytokine Production in Metastatic Renal Cell Carcinoma

Kleinknecht¹,

Kh²,

Wl³

1993

Urol Int

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Previous results on the peripheral blood immune status of renal cell carcinoma had indicated immunosuppression in metastatic disease, possibly mediated by prostaglandin E₂ (PGE₂). In the present study the immunologic effects of inhibition of PG synthesis by piroxicam in combination with interleukin 2 (IL 2) + lymphokine-activated killer (LAK) cell therapy were tested by immunomonitoring. In additon to peripheral blood parameters (lymphocyte subpopulations, neopterin, β₂-microglobulin, TNF, IL 1, IFNγ) we recorded in vitro cellular activity by incubating the patients’ peripheral blood mononuclear cells (PBMC) in media containing fetal calf serum (FCS) or autologous serum, and either IL 2 or buffer. After 24 h of incubation we measured PGE₂ and cytokine levels in supernatants. Systemic application of IL 2 induced in vivo lymphocyte proliferation and clearly influenced the serum levels of neopterin, β₂-microglobulin and TNF. There was minor affection of IFNγ and none of IL 1. PBMC in vitro produced high amounts of PGE₂, IL 1 and TNF pretherapeutically, during therapy in vitro synthesis of these parameters decreased. Consistent production of IFNγ was detected in supernatants only when FCS and IL 2 were added to the medium. Lack of affection of IFNγ production in the autologous system during therapy indicated impaired cellular activity, which could neither be improved by therapy of the patient using IL 2 nor by adding IL 2 to the culture medium. Immunosuppression seems to interfere in a complex way with immunotherapy. Therapeutical influence of immunosuppression based on the results of immunomonitoring, however, seems to be a promising strategy for improving the still limited clinical results of immunotherapy.

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Immune Status and Immune Therapy of Renal Cell Carcinoma

Cited by 18 publications

References 27 publications

Interleukin-6, tumour necrosis factor α and interleukin-1β in patients with renal cell carcinoma

Interleukin-6, tumour necrosis factor α and interleukin-1β in patients with renal cell carcinoma

Engagement of the inhibitory receptor CD158a interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction

Influence of Immunotherapy (IL2 + LAK + Inhibition of Prostaglandin Synthesis) on Peripheral Blood Immune Parameters and in vitro Cytokine Production in Metastatic Renal Cell Carcinoma

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