Prognostic value of cytotoxic T-lymphocyte-associated protein 4 expression and myeloid-derived suppressor cells in acute myeloid leukemia patients: correlation with cytogenetic mutations and treatment response

Background
Acute myeloid leukemia (AML) is a heterogeneous malignancy influenced by genetic, molecular, and immunological factors. It is a highly aggressive myeloid malignancy characterized by the arrest of myelopoiesis maturation, resulting in the accumulation of myeloblasts in the bone marrow and peripheral blood. In adult AML patients, standard chemotherapy frequently results in short-term complete remission. Nevertheless, under current treatment protocols, fewer than 50% of patients attain sustained remission. Targeting the immune system as a novel therapeutic strategy has demonstrated efficacy in various treatments, particularly those focused on immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which may augment innate immune responses to inhibit tumor proliferation. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells recognized for their ability to inhibit immune responses and proliferate in cases of cancer, infection, and inflammatory disorders. Despite the growing interest in MDSCs within tumor immunology, their varied functions in hematological malignancies relative to solid tumors are still poorly comprehended. Research into MDSCs in leukemia, particularly AML, has been limited.


Aim
This study aims to assess the prognostic significance of myeloid-derived suppressor cell levels and CTLA-4 expression in patients with newly diagnosed AML. It will examine their association with disease characteristics, response to induction chemotherapy, and established cytogenetic risk markers.


Patients and methods
A case–control study was conducted on 50 de novo adult AML patients and 50 healthy, age-, sex-, and BMI-matched controls, presented to the Hematology Department, Kafrelsheikh and Zagazig University Hospitals between March 2022 and June 2023. Clinical and laboratory assessments, including complete blood counts and bone marrow examination, were performed at diagnosis and after induction chemotherapy. CTLA4 expression and MDSC were assessed using real-time PCR and flow cytometry, while cytogenetic abnormalities were identified through standard molecular testing. MDSCs were detected in peripheral blood through mononuclear cell separation and flow cytometry. Programmed death-ligand 1 gene expression was assessed via RNA extraction, reverse transcription, and real-time PCR. Results for CTLA4 and MDSCs were then correlated with established genetic risk markers. Patients were classified based on their response to chemotherapy according to European LeukemiaNet guidelines 2022 into complete responders, partial responders, and nonresponders.


Results
CTLA4 expression and MDSC were significantly elevated in nonresponders compared with complete responders (P<0.001). Receiver operating characteristic curve analysis demonstrated that MDSC had excellent predictive accuracy for treatment response (area under the curve=1.00), while CTLA4 also showed strong predictive capability (area under the curve=0.85). A significant association was observed between high CTLA4 expression and nucleophosmin 1 and t (8,21) cytogenetic mutations, indicating a worse prognosis. In contrast, Fms-like tyrosine kinase 3 mutations were more frequently associated with patients exhibiting low CTLA4 expression (P=0.004).


Conclusion
CTLA4 and MDSC represent valuable prognostic biomarkers in AML. Their association with specific cytogenetic mutations highlights their potential role in predicting treatment response and patient outcomes. Integrating these biomarkers into routine clinical assessments may improve the stratification of AML patients and guide personalized therapeutic strategies.