The B7-H3 Protein In Acute Myeloid Leukemia

The B7 family of costimulatory molecules comprises several members, such as PD-L1 (B7-H1), that may participate in the immunoescape of tumor cells. For instance, the expression of PD-L1 in cancer cells can induce immunotolerance by deactivating T cells in several hematological malignancies, including acute myeloid leukemia (AML) and MDS. The B7-H3 (B7-homolog 3 or CD276) is a type I transmembrane protein and a member of the B7 family. B7-H3 is expressed in many tissues and in antigen-presenting cells. Its functions and counter receptor(s) remain unclear. The expression of the B7-H3 protein by the tumor microenvironment and tumor cells modifies the antitumor immune reaction, tumor growth, metastatic ability and drug resistance. B7-H3 is widely expressed in solid cancers and seems to be a prognostic marker in several tumor types. Clinical grade anti-B7-H3 antibodies are under development. The role of B7-H3 and its expression in AML has not yet been well investigated. We examined the expression of B7-H3 in the blast cells of a cohort of patients with AML to determine whether its expression affected the patients’ prognoses.

Our retrospective study included 111 patients (18 children and 93 adults) treated for AML between 2009 and 2011. We measured B7-H3 expression in bone marrow mononuclear cells using multiparameter flow cytometry (CD56, B7-H3, CD34, CD123, CD14, CD38 and CD45). We investigated the correlation of B7-H3 expression with biological, molecular and cytogenetic markers as well as the patient’s clinical characteristics. FLT3-ITD, NPM1 and CEBPA mutations were screened by the conventional Sanger methodology according to the ELN recommendations.

B7-H3 expression was low and invariable in lymphocytes and high in monocytes. According to the MFI (Mean Fluorescence Intensity) ratio of blasts/lymphocytes, the B7-H3 expression level in blasts was widely variable (0.80 to 10.38). The threshold retained in our study was 3. Twenty seven percent (30/111) of AML samples were positive, and positive samples primarily included the M5 and M3 FAB subtypes (50% of B7-H3 positive patients). The expression of B7-H3 did not correlate with age (p=0.86), sex (p=0.79), leucocytosis (p=0.38) or NPM1 mutation status (p=0.08). The expression of B7-H3 was significantly higher in adverse karyotypes (p<0.05). The expression of B7-H3 was significantly lower in CEBPA mutations (p<0.05) and tended to be lower in Core Binding Factors AML (p = 0.054). In the 54 adults who were treated with intensive chemotherapy, B7-H3 did not affect the complete remission (CR) rate (81% in B7-H3 negative group, 89% in B7-H3, positive group, p=0.62) or the overall survival (p=0.73).

B7-H3 is highly expressed in a substantial fraction of AML cases, which suggests that it could serve as a possible therapeutic target. The significant differences in the B7-H3 expression between the different subgroups of AML according to FAB, cytogenetic or CEBPA mutational status should encourage further screening of B7-H3 in a larger prospective cohort of AML patients to obtain definitive conclusions about its prognostic value.

Berthon:CELGENE: Research Funding. Preudhomme:CELGENE: Research Funding.