The tumor microenvironment in FL. (A) Gene expression profiling in FL identified 2 immune response signatures (IR1 and IR2) that can be used to predict clinical outcome. IR1 is associated with genes expressed by non-neoplastic T cells, whereas IR2 is associated with genes expressed by macrophages. Subsequent studies have analyzed specific cell populations within the tumor microenvironment. (B) Increased frequency of T_reg cells in the tumor microenvironment is generally associated with a favorable prognosis in FL, particularly when dispersed throughout the tumor. CCL22 secreted from lymphoma B cells induces the migration of CCR4⁺ T_reg cells and may in part account for the increased number of T_reg cells in FL. (C) T_FH cells overexpress IL-4, which induces signal transducer and activator of transcription 6 (STAT6) activation in neighboring malignant B cells. In addition, TAMs overexpress IL-15, which triggers STAT5-dependent FL B-cell activation. T_FH cooperate with this IL-15-mediated signal through CD40L-dependent transcriptional induction of STAT5. The transcriptional targets of STAT proteins play roles in cell cycle progression and cell survival. Therefore, T_FH and TAMs in the tumor microenvironment are generally associated with poor prognosis in FL.