In this issue of Blood, results from Veenstra et al highlight an important role of the B7-superfamily member B7-H3 (CD276) in allogeneic bone marrow transplantation.1 

(A) (Top) Transfer of allogeneic T cells into B7-H3–deficient animals leads to an increased GVHD lethality compared with the transfer of wild-type T cells. (Bottom) Transfer of B7-H3–deficient T cells into recipient animals results in stronger GVHD than transfer of wild-type T cells. (B) Because a delayed transfer of B7-H3–deficient lymphocytes is not associated with enhanced GVHD, these results indicate that blockade of B7-H3 during DLI might be a therapeutic measure to enhance GVL effects. Professional illustration by Patrick Lane, ScEYEnce Studios.

(A) (Top) Transfer of allogeneic T cells into B7-H3–deficient animals leads to an increased GVHD lethality compared with the transfer of wild-type T cells. (Bottom) Transfer of B7-H3–deficient T cells into recipient animals results in stronger GVHD than transfer of wild-type T cells. (B) Because a delayed transfer of B7-H3–deficient lymphocytes is not associated with enhanced GVHD, these results indicate that blockade of B7-H3 during DLI might be a therapeutic measure to enhance GVL effects. Professional illustration by Patrick Lane, ScEYEnce Studios.

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Costimulatory and coinhibitory pathways have a pivotal role in regulating T-cell responses. Several of the most important ligands to T-cell costimulatory and coinhibitory receptors like CD80 (B7-1), CD86 (B7-2), inducible T-cell costimulator ligand, and programmed death-ligands 1 and 2 (PD-L1 and PD-L2) belong to the B7 superfamily. B7-H3 is another member of this family, and activating as well as inhibitory functions have been ascribed to this molecule.

Veenstra et al have investigated the role of B7-H3 in a major histocompatibility complex (MHC)–mismatched bone marrow transplantation model.1  They found B7-H3 to be upregulated during graft-versus-host disease (GVHD) in the target organs in mice and also in the intestine of GVHD patients. Infusion of donor T cells into B7-H3−/− vs wild-type recipients resulted in increased T-cell proliferation, and higher GVHD lethality. Moreover, they demonstrate that B7-H3 deficiency in the infused T cells also led to increased GVHD lethality (see figure).

This study sheds new light on the functional role of B7-H3 in T-cell activation. Although it was initially described as an activating molecule that potently costimulates interferon gamma production in murine T cells,2  several more recent studies point to an inhibitory role of murine and human B7-H3.3-5  Veenstra et al provide additional evidence for an inhibitory function of this molecule by demonstrating that absence of B7-H3 increases T-cell proliferation in an allogeneic setting, thereby worsening GVHD.1  Moreover, stimulation of T cells with allogeneic dendritic cells lacking B7-H3 resulted in a stronger proliferative response. B7-H3 is upregulated in murine and human T cells upon activation,2,6  and B7-H3 deficiency in the donor T cells also led to an enhanced GVHD lethality. This indicates that B7-H3 is inhibitory not only on antigen-presenting cells, but also when expressed on T cells. B7-H3 has a short cytoplasmic tail that appears to be devoid of signaling domains. Therefore, this molecule is more likely to act as a ligand than as a receptor. Taking this into consideration, it is possible that T-cell–expressed B7-H3 triggers B7-H3 receptors in cis or in trans on T cells. Veenstra et al have performed in vitro stimulation assays to address this issue and came to the conclusion that B7-H3 does not inhibit in trans in a T–T-cell manner.1  However, the strong stimuli that were applied in their assay might have masked inhibitory effects of B7-H3 and the role of T-cell–expressed B7-H3 certainly warrants further in vitro and in vivo studies.

Collectively, this study points to a prominent role of B7-H3 as a negative regulator of acute T-cell–mediated graft-versus-host reactivity. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment option for patients with high-risk leukemias. Conditioning regimens given prior to HSCT are in many cases not sufficient to achieve durable remission, and donor lymphocyte infusion (DLI) is an important therapy to treat relapsing leukemia. The infused donor cells can exert a graft-versus-leukemia (GVL) effect but they often also cause GVHD. Previous murine studies have shown that blockade of coinhibitory molecules like programmed cell death protein 1 (PD1) or cytolytic T lymphocyte-associated antigen 4 (CTLA4) can enhance GVL effects without increasing GVHD severity.7,8  Veenstra used 2 different DLI models to demonstrate that B7-H3−/− splenocytes can also exert GVL activity without inducing GVHD. This could indicate that negative costimulatory molecules like PD1, CTLA4, and also B7-H3 are important to limit acute GVHD at the time of bone marrow transplantation, but blockade of these pathways at the time of delayed DLI might be a promising therapeutic measure to enhance GVL.

B7-H3 is expressed on various tumor cells and an Fc-enhanced B7-H3 antibody was developed9 ; it is currently being tested in cancer patients in a phase 1 clinical study (NCT01391143). B7-H3 antibodies that block the T-cell inhibitory effects of B7-H3 will target B7-H3–expressing tumor cells directly and will in addition enhance the efficacy of autologous T cells to fight tumor cells. The data presented in this study indicate that they might also have the potential to increase the ability of T cells to combat allogeneic leukemia cells (see figure). It will, however, be important to test blocking antibodies to B7-H3 in the DLI model used by Veenstra et al to assess whether they can enhance GVL without causing GVHD. The availability of well-defined powerful blocking reagents is a prerequisite for the development of therapeutic antibodies to human B7-H3 that can be used to enhance T-cell responses to solid tumor cells or to boost GVL effects of infused donor lymphocytes.

A better understanding of the biology of this B7 family member might help developing therapies targeting B7-H3 pathways. TLT-2 was proposed to function as a B7-H3 receptor but 2 independent studies could not confirm this interaction.4,10  Identification of B7-H3 receptors will help to understand the complex biological role of this molecule. In addition, they can be regarded as promising therapeutic targets not only to attenuate allogeneic responses in the context of GVHD but also to fortify T cells to better combat solid tumors or leukemia cells.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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