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1.
J Mol Med (Berl) ; 90(1): 55-66, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21870102

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is an aggressive and difficult to manage cancer. Immunotherapy has the potential to induce long-lasting regression in a small group of patients. However, severe side effects limit broad application which highlights the need for a marker to distinguish responder from nonresponder. TNMG staging, referring to tumor size, lymph node involvement, presence of metastasis, and grade of tumor differentiation, represents an important prognostic system but is not useful for predicting responders to immunotherapy. NK cells are potent antitumor effector cells, and a role as prognostic marker in some solid tumors has been suggested. As NK cells are responsive to various immune modifiers, they may be important mediators of patient response to immunotherapies, in particular those including IL-2. We report that the NK cell percentage within RCC-infiltrating lymphocytes, as determined by flow cytometry, allows ccRCC subgrouping in NK(high)/NK(low) tissues independent of TNMG classification. Quantitative reverse transcriptase polymerase chain reaction using whole-tissue RNA identified four markers (NKp46, perforin, CX(3)CL1, and CX(3)CR1) whose transcript levels reproduced the NK(high)/NK(low) tissue distinction identified by flow cytometry with high selectivity and specificity. Combined in a multiplex profile and analyzed using neural network, the accuracy of predicting the NK(high)/NK(low) groups was 87.8%, surpassing that of each single marker. The tissue transcript signature, based on a robust high-throughput methodology, is easily amenable to archive material and clinical translation. This now allows the analysis of large patient cohorts to substantiate a role of NK cells in cancer progression or response to immunotherapy.


Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Gene Expression Profiling , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Killer Cells, Natural/pathology , Adult , Aged , Aged, 80 and over , CX3C Chemokine Receptor 1 , Carcinoma, Renal Cell/classification , Carcinoma, Renal Cell/mortality , Chemokine CX3CL1/genetics , Female , Humans , Immunophenotyping , Kidney Neoplasms/classification , Kidney Neoplasms/mortality , Lymphocytes, Tumor-Infiltrating/pathology , Male , Middle Aged , Natural Cytotoxicity Triggering Receptor 1/genetics , Neoplasm Staging , Perforin/genetics , Prognosis , Receptors, Chemokine/genetics
2.
Am J Pathol ; 179(1): 436-51, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21703422

ABSTRACT

Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209(+) DCs in RCCs was found to be associated with an unfavorable T(H)1 cell balance in the tissue and advanced tumor stages. The CD209(+) DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for T(H)1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC.


Subject(s)
Carcinoma, Renal Cell/immunology , Dendritic Cells/immunology , Kidney Neoplasms/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , Apoptosis , Blotting, Western , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Case-Control Studies , Cell Differentiation , Cell Movement , Cell Proliferation , Chemokines/metabolism , Cross-Priming , Cytokines/metabolism , Dendritic Cells/metabolism , Dendritic Cells/pathology , Endocytosis , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Interleukin-6/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , Phagocytosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Tumor Cells, Cultured
3.
Am J Clin Pathol ; 122(4): 560-5, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15487454

ABSTRACT

In patients with mastocytosis, gastrointestinal symptoms are a frequent phenomenon. However, there are only limited data about the quantity and distribution pattern of mast cells in the gastrointestinal mucosa. We stained gastroduodenal biopsy specimens from 27 patients with mastocytosis and 48 control subjects for mast cell tryptase, CD117, and CD25. The numbers of mucosal mast cells per high-power field showed wide variation in all groups and were decreased markedly in biopsy specimens of corpus and duodenum and statistically significantly decreased in antrum biopsy specimens from patients with systemic mastocytosis compared with patients with pure urticaria pigmentosa and with control subjects. Staining for tryptase showed highly significant correlation with staining for CD117. All mast cells were negative for CD25, which is expressed characteristically by neoplastic mast cells. Causes of the decrease of mucosal mast cells remain enigmatic, but our results show that gastrointestinal symptoms of patients with mastocytosis are most likely mediator-related and not due to an increase of local mast cells.


Subject(s)
Gastric Mucosa/pathology , Intestinal Mucosa/pathology , Mast Cells/pathology , Mastocytosis, Systemic/pathology , Adult , Aged , Humans , Middle Aged , Proto-Oncogene Proteins c-kit/analysis , Receptors, Interleukin-2/analysis , Serine Endopeptidases/analysis , Tryptases
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