title: Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging.
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.
authors.affiliation: Clinical Cooperation Group "Immune Monitoring", Institute of Molecular Immunology, Helmholtz Zentrum München-German Research Center for Environmental Health, Marchioninistrasse 25, 81377 Munich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Eckl
authors.forename: Alexander
authors.initials: A
authors.lastname: Buchner
authors.forename: Petra U
authors.initials: PU
authors.lastname: Prinz
authors.forename: Rainer
authors.initials: R
authors.lastname: Riesenberg
authors.forename: Sabine I
authors.initials: SI
authors.lastname: Siegert
authors.forename: Robert
authors.initials: R
authors.lastname: Kammerer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000073883:CX3C Chemokine Receptor 1; D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D054428:Chemokine CX3CL1 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D007694:Killer Cells, Natural / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics; D009367:Neoplasm Staging; D054353:Perforin / Q000235:genetics; D011379:Prognosis; D019707:Receptors, Chemokine / Q000235:genetics
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D019707:Receptors, Chemokine; D054353:Perforin