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.1 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 FoxP3-positive Treg cells.2Malignant cells also express PD-L1, and interactions with PD1 expressed on intratumoral immune cells results in immune suppression.3,4 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.5 Treg cells recruited to sites of lymphoma have been shown to suppress both effector CD8+ T cells and intratumoral CD4+ cells.5,6 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.7,8 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.8 Overall, malignant B cells skew the T-cell balance within lymph nodes promoting Treg cells and inhibiting effector T cells or TH17 cells.
In the article that accompanies this editorial, Kiaii et al10 contribute to this growing body of literature by showing that follicular lymphoma B cells induce changes in gene expression in intratumoral T cells that results in changes in T-cell function. In addition, they show that T cells exhibiting genetic changes induced by lymphoma cells significantly impact the outcome of patients with follicular lymphoma as well as the risk of transformation to large-cell lymphoma. The authors also investigated the molecular mechanisms whereby tumor-infiltrating T cells are changed within the tumor microenvironment. To do this they used highly purified CD4+ and CD8+ T cells from malignant lymph nodes from patients with follicular lymphoma obtained at the time of diagnosis before therapy. These cells were compared with cells from control tissues, including reactive lymph nodes and peripheral blood. They were able to show that intratumoral CD8+ and CD4+ T lymphocytes had a genetic signature that was different from normal CD4+ and CD8+ T cells. Importantly, they could also show that when healthy allogeneic T cells were cocultured with purified lymphoma B cells, a gene expression pattern similar to that seen in intratumoral T cells, was induced. The changes in gene expression seemed to be caused by both direct contact between T cells and malignant B cells and by soluble factors. This supports the previous findings that both secreted and cell surface ligands are important in defining the tumor microenvironment in follicular B-cell lymphoma. Because ACTN1 was among the most downregulated genes in intratumoral T cells and actin-based motility signaling pathways seemed disrupted, the authors evaluated the motility of sorted CD4+ and CD8+ tumor infiltrating lymphocytes. When compared with normal controls, intratumoral T cells were functionally impaired with a significant reduction in their motility index when compared with normal controls. In a multivariable prognostic model, the authors then showed that the number and location of T cells expressing PMCH, NAMPT, and ETV1 had prognostic significance and were associated with both overall survival and the time to transformation to large-cell lymphoma. These data confirm the important role that malignant B cells play in defining the function and differentiation of intratumoral T cells. These results also confirm that the number and location of lymphoma infiltrating lymphocytes is associated with patient outcome.
These findings are particularly important as novel T-cell–mediated therapies are being developed for B-cell malignancies. Whereas T cells can mediate antitumor responses in lymphoma patients, the immune tolerance mechanisms described above often result in deletion or inactivation of tumor-specific T cells. To overcome this problem, genes encoding an antibody against a lymphoma-associated antigen such as CD19 have been linked, in the form of a single-chain variable fragment, to genes that encode T-cell signaling domains. This chimeric antigen receptor (CAR) has then been introduced into T cells and these cells used for adoptive T-cell therapy.11 CAR T cells are able to recognize tumor antigens in a HLA-independent manner and this allows CAR-modified T cells to overcome the tumor’s ability to escape immune detection by downregulation of HLA expression. Initial use of CAR T cells resulted in encouraging clinical responses,12 however the clinical utility of particularly the first-generation CAR T cells was limited by their inability to sufficiently activate and sustain themselves in vivo. The subsequent generations of CAR T cells—with the addition of costimulatory domains to the intracellular portion including CD28, 4-1BB, or OX40—have been engineered to enhance cytokine secretion and effector cell expansion and to prevent activation-induced apoptosis and immune suppression by the tumor. Despite these modifications, the best clinical results have been seen in patients with a low tumor burden and in those who first received cytotoxic chemotherapy before CAR T-cell therapy.13 The chemotherapy administered was likely to have not only depleted malignant cells but also decreased immunosuppressive cells such as Treg cells and suppressive monocytes. Malignant B cells, and the immunosuppressive tumor microenvironment they promote, may therefore remain a barrier to effective adoptive immunotherapy in B-cell lymphoma, particularly in patients with chemotherapy-resistant, bulky disease.
Malignant B cells in follicular lymphoma clearly play a defining role regarding the composition and function of the tumor microenvironment. The data presented confirm that malignant B cells promote a profoundly immunosuppressive microenvironment and thereby protect themselves from being targeted by the immune system. Future therapies in follicular lymphoma, including immunotherapies such as CAR T cells, will need to not only deplete malignant B cells but also inhibit the immunosuppressive mechanisms by which malignant B cells suppress the antitumor immune response. A dual approach that both depletes malignant cells and promotes immune function may subsequently result in a better clinical outcome for patients with follicular lymphoma.