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.

ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy

“…Natural killer (NK) cells play an important role as first-line defenders in the host response to tumors and infections, in transplant rejection, and the development of tolerance (5). The presence of intratumoral NK in RCC correlates with improved patient survival (6). Recent studies suggest that immunotherapy may be an effective approach for patients with RCC (7), and emerging strategies are currently under investigation based on adoptive transfer of T or NK cells (8,9).…”

Expansion of CMV-Mediated NKG2C+ NK Cells Associates with the Development of Specific De Novo Malignancies in Liver-Transplanted Patients

“…In contrast, the presence of immature NK cells in 2C 2 leads to the development of de novo genitourinary tumors. Further investigations with larger numbers of patients are required to confirm these hypotheses; nonetheless, the findings that Marc-Olivier Bitker, 3 Alain Chapelier, 4 Jean-Paul Couetil, 2 Philippe Dartevelle, 5 Michel Delahousse, 4 Philippe Deleuze, 6 Bertrand Dousset, 7 Denis Glotz, 1 Laurent Hannoun, 3 Philippe Lang, 2 Francoise Le Pimpec Barthes, 8 Patrick Nataf, 9 Patrick Niaudet, 10 Jean-Jacques Patard, 11 Alain Pavie, 3 Eric Rondeau, 12 Didier Samuel, 13 Emmanuel Tiret, 14 Dominique Valla, 15 Coordinator for epidemiology: Caroline Besson 11 Coordinators for immunology: Patrice Debré, 16 Antoine Toubert, 1 and Vincent Vieillard 16 Coordinators for pharmacogenetics: Laurent Puig, 8 Laurent Thervet …”

“…An 11-y generalpopulation follow-up study showed that high NK cytotoxic activity is associated with reduced risk of cancer (7). In addition, NK cell infiltration into tumor tissues is associated with better disease prognosis in non-small-cell lung carcinoma (8), renal cell carcinoma (9), and colorectal carcinoma (10). NK cells are heterogeneous and differ in their proliferative potential, homing characteristics, functional capacities, and responses to different cytokines.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Poor Poor (Dannenmann et al, 2013;Komohara et al, 2011;Xu et al, 2014) Good (Donskov, 2007;Eckl et al, 2012) Prostatic adenocarcinoma…”