The Surface-Exposed Nuclear Speckle Protein SRRM2 Confers a Novel Target Molecule for the Immunotherapy of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a serious, life-threatening and hardly curable hematological malignancy with a 5-year survival rate of only about 30%. CAR T-cell therapy has emerged as a highly effective option for the treatment of B-cell malignancies. Serine/arginine repetitive matrix 2 (SRRM2) is a nuclear speckle protein involved in RNA splicing that may contribute to survival of blast cells and drug resistance in AML. Interestingly, we recently identified SRRM2 on the surface of malignant cells, including AML blasts. Here, we investigated the specific level and characteristics of SRRM2 protein expression in AML patients and whether the protein can serve as a target antigen for AML treatment.

In this study, we detected and analyzed the expression and cellular localization of SRRM2 in AML cell lines and patients newly diagnosed/relapsed with AML using a proprietary SRRM2-specific antibody (EX02). Subsequently, a second-generation CAR-T cell targeting SRRM2 was constructed, and the efficacy and safety of SRRM2 CAR-T cells were assessed in vitro and in vivo using a NSG mouse model of AML.

Our results show that SRRM2 is exposed at the surface of most blast cells from various types of AML cell lines and patients with AML, and that the level of surface SRRM2 directly correlates to high risk, relapse and poor prognosis. Even more important, in normal hematopoietic stem cells and differentiated mature blood cells, as well as in normal tissues from lung etc., SRRM2 was only found to be located in the nucleus. Finally, SRRM2 CAR-T cells exhibited significantly elevated secretion of IFN-γ and TNF-α and enhanced cytotoxicity against AML cell lines. In the AML mouse model, SRRM2 CAR-T cells displayed significant suppression on AML and extended survival.

Collectively, we demonstrated that the ectopic exposure of the SRRM2 protein on the surface of AML cells constitutes an attractive target molecule for the development of targeted therapies against AML, like SRRM2-specific CAR-T cells.

The use of human material for these investigations was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (NO. YJ-YX2019-015).

No relevant conflicts of interest to declare.