Follicular lymphoma and the immune system: from pathogenesis to antibody therapy

Abstract

Follicular lymphoma (FL) is a B-cell tumor arising in germinal centers and retaining features of its normal B-cell counterpart.Lymphomagenesis appears stepwise from the t(14;18) translocation, through FL-like cells, to FL in situ, then to overt FL. Surface Ig is mandatory and carries a striking V-region modification because of introduction of glycan addition sites during somatic mutation. These are positively selected and acquire unusual high mannoses, which interact with lectins.The Ig-associated mannoses appear essential for FL, providing a diseasespecific target for antibody attack. Antibody therapy is currently focused on anti-CD20 (rituximab), which appears to rely predominantly on the Fc␥ module recruiting suitably activated macrophages. Immunogloblulin and, to some extent, CD20, can each escape antibody attack in vitro by modulation, but this is difficult to demonstrate clinically. Instead, studies of anti-CD20 therapy of FL suggest that effector modulation, similar to that seen in the suppression of autoimmune inflammation by infusions of normal human IgG, may be important. Both antigenic and effector modulations might be minimized by repeated small doses of more potent antibodies. Clearly, mechanisms of attack vary with the malignancy, the target molecule, and the antibody design, offering opportunities for optimizing this promising strategy. (Blood. 2012;119(16): 3659-3667) IntroductionAntibody is now a major contributor to the treatment of B-cell malignancies. However, there remains a pressing need to understand better how to encourage the destruction of antibody-coated neoplastic cells. We direct our attention to human follicular lymphoma (FL), to its pathogenesis and a therapeutic opportunity this reveals. We focus on 2 of its cell-surface antigens: first, the key receptor of B cells, surface immunoglobulin (Ig), which has a renewed target potential; and second, an established target, CD20. Antibodies against each molecule are clinically effective but may differ in the mechanism of killing. They differ in susceptibility to endocytosis/modulation after engagement by antibody and illustrate the need to understand the behavior of the target molecule to optimize strategies for attack. Development of FLFL occupies the immune system, surviving and proliferating mainly in the germinal centers (GCs) of lymph nodes. The architecture of normal GCs tends to be retained, with lymphoma cells located in a network of follicular dendritic cells, follicular CD4 ϩ T cells, and stromal elements. For normal B cells, GCs are the sites where Darwinian evolution occurs with binding to antigen being the positive selector and death awaiting nonselected B cells. To persist in this hostile environment, FL cells need to escape the default death pathways. One protective factor evident in the majority of cases is the up-regulated expression of the antiapoptotic BCL2 protein via the t(14;18)(q32;q21) translocation. The translocation appears to occur principally as an error during Ig VDJ recombination in the bone marrow, which pla...

Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells

“…Thus macrophages may promote tumor growth but, as mediators of antibody-dependent cellular cytotoxicity, they are required for antibody therapy. 25 The positively selected expression of high mannose in the sIg variable regions is a clue to pathogenesis, 26 and strongly indicates an essential interaction with a presumed lectin in the lymph node. It appears that mannosylation motifs are acquired at the early stage of lymphomagenesis, termed "follicular lymphoma in situ."…”

The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

“…1,2 As for other B-cell malignancies, the molecular nature of the sIg in chronic lymphocytic leukemia (CLL) has provided insight into the development and pathogenesis of the disease. We recently reviewed this topic 3 and will summarize it only briefly here.…”

Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma

“…1 FL has a varied clinical course that is influenced by FL cell-intrinsic and cell-extrinsic aberrations, and FL remains incurable using conventional therapies. [2][3][4][5][6] Genetically, FL is characterized by the hallmark balanced chromosomal translocation t (14;18), found in about 85% of FL cases, leading to deregulated expression of BCL2. [7][8][9] A subtype of FL (;15%) that lacks translocation t(14;18) has also been described.…”