CCR7 & lymphotoxin in lymphoma niche

The role of microenvironmental interactions in lymphoma growth is increasingly being recognized but still poorly understood. In this issue of Blood, Rehm and colleagues used a mouse model of aggressive B-cell lymphoma to show that the chemokine receptor CCR7 plays a pivotal role in homing of tumor cells into lymphoma-supporting niches in secondary lymphoid organs, and that lymphotoxin signaling is involved in a tumor-promoting reciprocal interaction between lymphoma cells and fibroblastic reticular cells in these niches.¹ 

The role of genetic lesions in the pathogenesis of B-cell lymphomas is well appreciated.²  We know now multiple transforming events that play key roles in the generation of malignant B cells. For example, chromosomal translocations involving one of the immunoglobulin (Ig) loci and a proto-oncogene are a hallmark of many lymphomas, such as Ig-Myc translocations in Burkitt lymphoma and Bcl2-IgH translocations in follicular lymphoma.²  Although translocations and other mutations are essential for the malignant transformation of lymphocytes and the generation of a monoclonal neoplastic cell population, there is increasing evidence that microenvironmental interactions are also critical for the growth and survival of the lymphoma cells.^2,3  For example, in follicular lymphoma the transformed germinal center B cells remain largely restricted to follicular structures. This indicates that the interaction with follicular dendritic cells, follicular T helper cells, and perhaps other cellular components of B-cell follicles are not only essential for the survival and proliferation of normal germinal center B cells, but also for the follicular lymphoma tumor cells.^2,3  In addition, in classic Hodgkin lymphoma, the tumor cells are found in a typical microenvironment composed of many different types of cells of the hematopoietic system, and there is ample evidence that the malignant cells are dependent on this microenvironment.⁴  Thus, it is highly relevant to better understand how lymphoma cells find and modify their niches in lymphoid organs and through which mechanisms the lymphoma cells and microenvironmental nontumor cells interact.

Rehm et al used a mouse model of Myc-driven aggressive B-cell progenitor lymphoma to study these issues.¹  They were particularly interested in the role of the chemokine receptor CCR7 in the homing of the lymphoma cells to secondary lymphoid organs, because CCR7 is a homeostatic chemokine receptor that controls the homing of CCR7-positive cells into the T-cell region of lymph nodes and the spleen.⁵  The ligands for CCR7, CCL19 and CCL21, are expressed by stromal cells in secondary lymphoid organs. To study the role of CCR7 in their genetic model, the authors generated Myc transgenic mice deficient for CCR7. CCR7-positive and -negative lymphoma cells were used for transfer experiments into congenic mice, which allowed a detailed study of the growth kinetics and numerous other features of the lymphoma cells. It is shown that CCR7 indeed regulates homing of the lymphoma cells to T cell regions in lymph nodes and the spleen, and that CCR7-positive lymphoma cells had a survival advantage compared with CCR7-deficient lymphoma cells. Within the niches, the lymphoma cells interacted with fibroblastic reticular cells in a reciprocal fashion. This cross-talk involved stimulation of the lymphotoxin β receptor–expressing reticular cells through lymphotoxin secreted by the lymphoma cells (see figure). The survival of the lymphoma B cells within their niche was presumably promoted by Indian hedgehog secreted by fibroblastic reticular cells and by stimulation of the CD40 receptor on lymphoma cells through CD40 ligand–expressing CD4⁺ T cells. The importance of this cross-talk was demonstrated by showing that its inhibition impaired lymphoma growth.

The relevance of CCR7 as a homing receptor for tumor cells goes well beyond the model of Myc-driven B-cell precursor lymphoma as studied in the work by Rehm and colleagues. In a mouse model of primary central nervous system T-cell leukemia, it was recently shown that CCR7 is an essential regulator of leukemia cell infiltration into the central nervous system.⁶  In human T-cell leukemias, high CCR7 expression was found to be associated with lymphatic and distant dissemination in the patients and with tumor cell migration and invasion in vitro.⁷  Notably, CCR7 is not only implicated in lymphoid neoplasias, but also in solid cancers, where it may promote metastasis of cancer cells into lymphoid organs and other CCL19/CCL21-secreting tissues.⁸ 

Better insights into the migration and dissemination behavior of lymphoma cells and of the microenvironmental interactions in lymph node niches, as studied in the elegant work by Rehm and colleagues, is not only of relevance for basic lymphoma research, but also has clinical implications. If we better understand on which microenvironmental factors and interactions lymphoma cells depend for their survival, growth, and dissemination, it may be possible to develop novel therapeutic approaches that interfere with these tumor-promoting factors. The growth-inhibiting effects of interference with the lymphotoxin/lymphotoxin-receptor axis or the hedgehog signaling pathway in the study by Rehm et al represent intriguing examples in this direction.