The role of B7 family molecules in hematologic malignancy

Abstract

IntroductionCancer and the immune system are fundamentally interrelated. 1,2 Cancer cells express tumor-specific aberrant antigens 3,4 and must therefore evade immune detection to survive, 5 either by inducing immunosuppression 2 or deriving survival signals from tumor-infiltrating immune cells. 6 T cell-mediated antitumor immunity 4 requires recognition of cancer-associated antigen by the major histocompatibility complex (MHC), and appropriate costimulatory and repressive secondary signals arising from complex interactions with other immune, stromal, and tumor cells. Dysfunction of costimulation pathways may contribute to failed antitumor immunity.The B7 system (Table 1) is one of the most important secondary signaling mechanisms and is essential in maintaining the delicate balance between immune potency and suppression of autoimmunity. Potential therapeutic applications include immune-boosting adjuvants to conventional anticancer therapy, hematopoietic stem cell transplantation (HSCT), antitumor vaccines, bioengineered T cells as well as attenuation of graft-versus-host disease (GVHD). The B7 family is only one aspect of a complex signaling network (Figures 1 and 2) that comprises other immunoglobulin superfamily (IGSF) members, the tumor necrosis factor superfamily (TNFRSF), chemokines, cytokines, and adhesion molecules. However, based on a substantial evidence base and a growing therapeutic armory, the B7 family requires particular attention, as summarized in Table 2.7 The standardized approach to nomenclature is the cluster of differentiation (CD), which has not yet been applied to all members of the family. While many researchers are more familiar with their original names, which are still widely used in the literature, for the purposes of this review, the CD designation is used wherever possible. B7 founder members CD80, CD28, and CD152 (CTLA-4)The first B7 family member was a molecule discovered on activated, proliferative splenic B lymphocytes, 7 and termed B7 in an early nomenclature convention attributed to B cell-defining markers. Subsequent cloning and sequencing of the B7 gene revealed sequence homology with IGSF members and expression in a variety of lymphoid malignancies. 8 B7 was found to bind CD28, 9 an IGSF member on T cells, which augmented their activation. [10][11][12] Further molecular profiling identified a CD28 homologue, CD152 (cytolytic T cell-associated sequence-4 [CTLA-4]), 13 which mapped to the same chromosomal region as CD28 14 and bound B7 more potently. 15 The B7 signal blockade using a CTLA-4.Ig construct led to suppression of humoral 16 and cellmediated immune responses, 17 while transfection of immunogenic murine melanoma cell lines with B7 enhanced antitumor immunity, which could be abrogated by CTLA-4.Ig. 18 Initial experiments suggested that both anti-CD28 and anti-CTLA-4 monoclonal antibodies (mAbs) were T-cell activators, 19 but contrary evidence showing a suppressive role for CTLA-4 soon emerged 20,21 and was conclusively demonstrated in Ctla-4 Ϫ/Ϫ mice, which rapidl...

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

“…42 However, almost none of the relevant review articles include BTLA as a B7-H4 receptor. 10,[43][44][45][46][47][48][49][50] Our findings provide additional support for the role of BTLA as a B7-H4 receptor.…”

The role of B7 family costimulatory molecules and indoleamine 2,3-dioxygenase in primary Sjögren’s syndrome and systemic sclerosis

“…The B7 family is one of the most important second signal mechanisms and is essential to the maintenance of the delicate balance between immune potency and suppression of autoimmunity. The importance of the B7 family in regulating immune responses is clear from their demonstrated role in the development of immunodeficiency, cancer, and autoimmune diseases [22]. Manipulation of the signals delivered by B7 ligands shows a great potential in the treatment of cancer or autoimmune disorders including pSS and SSc.…”

PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia

“…2 Programmed cell death 1 (PD-1; CD279) and its ligands programmed death-ligand 1 (PD-L1; B7-H1; CD274) and PD-L2 (B7-DC; CD273) constitute one of the most prominent immune checkpoint ligand/receptor axes involved in providing and maintaining an immunosuppressive tumor microenvironment. 3 Under physiological conditions, PD-1 is temporarily expressed on immune effector cells upon their activation. Binding of PD-1 by PD-L1 or PD-L2 on antigen-presenting cells results in inhibition of proliferation, cytokine production, and cytotoxic capabilities of T cells.…”