It has been shown that CD4 and CD8 tumor-infiltrating lymphocytes in follicular lymphoma have impaired function and suppressed recruitment of critical signaling proteins to the immunologic synapse, and a number of studies have indicated the prognostic importance of the immune microenvironment in follicular lymphoma. In a study reported in the Journal of Clinical Oncology,1 Shahryar Kiaii, PhD, of Barts Cancer Institute, London, and colleagues investigated the molecular mechanisms underlying changes in tumor-infiltrating lymphocytes in the follicular lymphoma microenvironment. They found that the cells exhibited altered gene expression and showed that changes in the microenvironment can affect overall survival and time to transformation in follicular lymphoma.
The study involved gene-expression profiling of highly purified CD4 and CD8 tumor-infiltrating lymphocytes from lymph node biopsies at time of diagnosis in treatment-naive patients with follicular lymphoma and from reactive tonsils and peripheral blood from healthy subjects. Diagnostic tissue microarrays from an independent patient set were used to verify protein expression and analyze the impact of tumor-infiltrating lymphocyte–expressed genes on outcome, and time-lapse imaging was used to assess T-cell motility.
Upregulated Genes and Impaired Motility
The most upregulated genes in both CD4 and CD8 tumor-infiltrating lymphocytes were PMCH, ETV1, and TNFRSF9. PMCH was not expressed in peripheral blood T cells, but its expression was highly induced when cells were cocultured with follicular lymphoma cells. Both CD4 and CD8 tumor-infiltrating lymphocytes from patients with follicular lymphoma exhibited significantly impaired motility compared with the healthy tumor-infiltrating lymphocytes from reactive tonsils, and impairment of motility could be induced in healthy T cells by exposure to follicular lymphoma cells.
Models incorporating the number and location of T cells expressing PMCH, NAMPT, and ETV1 showed prognostic significance for overall survival and time to transformation. In particular, the best model for predicting improved overall survival consisted of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the ratio of ETV1-expressing cells in the interfollicular/intrafollicular area; a high combined score identified patients with significantly improved overall survival (hazard ratio [HR] = 0.32, P = .007).
A model combining the ratio of PMCH-expressing cells in the interfollicular/intrafollicular area combined with high expression of NAMPT and low expression of ETV1 in the intrafollicular area best identified patients with longer time to transformation (HR = 0.19, P = .003).
The investigators concluded, “[O]ur findings improve our understanding of the impact of tumor-infiltrating T cells in the microenvironment, identify molecular pathways that are altered, and introduce novel genes that may affect follicular lymphoma biology and outcome.” ■
Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.
1. Kiaii S, Clear AJ, Ramsay AG, et al: Follicular lymphoma cells induce changes in T-cell gene expression and function: Potential impact on survival and risk of transformation. J Clin Oncol. June 17, 2013 (early release online).