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Malignant B cells at the helm in follicular lymphoma.

Lymph nodes in patients with follicular lymphoma contain not just malignant B cells but normal immune cells including T cells, intratumoral macrophages, monocytes, dendritic cells, and natural-killer cells. Recent data have shown that the tumor microenvironment plays an important role in the outcome of patients with non-Hodgkin lymphoma and that the composition of the microenvironment has prognostic significance for patients with follicular lymphoma. It is becoming increasingly clear that, although the tumor microenvironment supports the growth and survival of malignant B cells, the malignant B cells also define the constitution of the tumor microenvironment. Malignant B cells from biopsies of tumors in patients with lymphoma do not play a passive role but instead clearly drive the differentiation and function of intratumoral T cells (Fig 1). Malignant B cells have been found to express multiple ligands responsible for inducing regulatory T cells (Treg cells) and suppressing other intratumoral effector cells. Lymphoma B cells have been found to express CD70, and CD70/CD27 signaling promotes the induction of FoxP3positive Treg cells. 2 Malignant cells also express PD-L1, and interactions with PD1 expressed on intratumoral immune cells results in immune suppression. B cells from lymphoma biopsies have been found to secrete chemokines and cytokines responsible for further immune suppression. CCL22 secreted by lymphoma B cells is involved in chemotaxis and migration of intratumoral Treg cells that express the receptor CCR4, which results in recruitment of Treg cells to the tumor microenvironment. Treg cells recruited to sites of lymphoma have been shown to suppress both effector CD8 T cells and intratumoral CD4 cells. Cytokines and chemokines such as interleukin 12 and CXCL10 produced by the malignant B cells also have a role in regulating effector T-cell function. However, interleukin 12 has been shown to induce T-cell exhaustion, resulting in ineffective T cells that are unable to proliferate or lyse target B cells. Overall, malignant B cells skew the T-cell balance within lymph nodes promoting Treg cells and inhibiting effector T cells or TH17 cells. 9