MRC2: A tumor-restricted surface antigen for immunotherapy in Acute Myeloid Leukemia

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with limited treatment options and poor outcomes. Progress in AML immunotherapy is hampered by the scarcity of tumor-specific antigens. Mannose receptor C-type 2 (MRC2), largely restricted to the myeloid lineage, contributes to immune regulation, but its utility as a tumor-restricted surface antigen and immunotherapeutic target is yet to be determined. Methods Membrane proteomics was performed on leukemia blasts from AML patients and normal hematopoietic cells from healthy donors. Potential membrane targets were then characterized by flow cytometry, immunofluorescence, and immunohistochemistry across AML cell lines, primary AML blasts, and normal counterparts. Their clinical relevance was further corroborated by integrated analyses of patient-derived datasets. Then, functional experiments experiments were conducted in vitro and in vivo. Results MRC2 was identified as a significantly overexpressed membrane protein in AML, a discovery corroborated in both primary patient-derived AML blasts and established AML cell lines. MRC2 expression remained negligible across diverse normal blood cells, hematopoietic stem cells, and was entirely undetectable in healthy human tissues. Elevated cell membrane surface MRC2 levels were associated with complex chromosomal karyotypes, adverse molecular risk stratification, diminished complete remission rates, and shortened relapse-free survival in AML cohorts. Functional assays confirmed MRC2's critical role in sustaining AML cells proliferation, clonogenic potential, and migratory capacity. Conclusion MRC2 is a functionally protein exhibiting restricted expression on AML cell membranes, suggesting its utility as an immunotherapy target. Future strategies to improve the prognosis of AML patients may include CAR-T therapy or antibody therapy targeting the cell surface protein MRC2. This work was supported by grants from General Projects of Natural Science Foundation of Anhui Province (No.2208085MH217) and Anhui Clinical Medical Research and Translational Project (No.202427b10020036).