Signal transducers and activators of transcription 5a-dependent cross-talk between follicular lymphoma cells and tumor microenvironment characterizes a group of patients with improved outcome after R-CHOP.

PURPOSE Tumor microenvironment has a strong effect on the survival of follicular lymphoma (FL) patients. The aim of this study was to determine what are the signaling pathways that mediate the cross-talk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the clinical outcome of FL patients. EXPERIMENTAL DESIGN Gene expression profiling and pathway impact analyses were done from pretreatment lymphoma tissue of 24 patients. The findings were validated immunohistochemically in an independent cohort of 81 patients. All patients were treated with the combination of rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone chemotherapy. In addition, microarray was used to screen the genes differentially expressed between control and rituximab-stimulated B-cell lymphoma cells in culture. RESULTS Among the transcripts differentially expressed in the FL tissues between the patients with favorable or adverse outcomes, an overrepresentation of genes associated with the signal transducers and activators of transcription (STAT)5a pathway was observed. In a validation set, a better progression-free survival was observed among the patients with high STAT5a protein expression. In the FL tissue, STAT5a positivity was barely detectable in the neoplastic B cells, but a subpopulation of follicular dendritic cells and T lymphocytes showed prominent STAT5a expression. Rituximab was found to induce the expression of STAT5a-associated interleukin-15 in B-lymphoma cells in culture, thereby providing a possible explanation for the cross-talk between rituximab-stimulated FL cells and their microenvironment. CONCLUSION The findings suggest that STAT5a activity in immunologically active nonmalignant cells acts as molecular predictor for rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone-treated FL patients.