CD8 + T cell-based molecular subtypes with heterogeneous immune landscapes and clinical significance in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Although high-dose chemotherapy is the primary treatment option, it cannot cure the disease, and new approaches need to be developed. The tumor microenvironment (TME) plays a crucial role in tumor biology and immunotherapy. CD8 + T cells are the main anti-tumor immune effector cells, and it is essential to understand their relationship with the TME and the clinicopathological characteristics of AML.

In this study, we conducted a systematic analysis of CD8 + T cell infiltration through multi-omics data and identified molecular subtypes with significant differences in CD8 + T cell infiltration and prognosis. We aimed to provide a comprehensive evaluation of the pathological factors affecting the prognosis of AML patients and to offer theoretical support for the precise treatment of AML.

Our results indicate that CD8 + T cell infiltration is accompanied by immunosuppression, and that there are two molecular subtypes, with the C2 subtype having a significantly worse prognosis than the C1 subtype, as well as less CD8 + T cell infiltration. We developed a signature to distinguish molecular subtypes using multiple machine learning algorithms and validated the prognostic predictive power of molecular subtypes in nine AML cohorts including 2059 AML patients. Our findings suggest that there are different immunosuppressive characteristics between the two subtypes. The C1 subtype has up-regulated expression of immune checkpoints such as CTLA4, PD-1, LAG3, and TIGITD, while the C2 subtype infiltrates more immunosuppressive cells such as Tregs and M2 macrophages. The C1 subtype is more responsive to anti-PD-1 immunotherapy and induction chemotherapy, as well as having higher immune and cancer-promoting variant-related pathway activity. Patients with the C2 subtype had a higher FLT3 mutation rate, higher WBC counts, and a higher percentage of blasts, as indicated by increased activity of signaling pathways involved in energy metabolism and cell proliferation. Analysis of data from ex vivo AML cell drug assays has identified a group of drugs that differ in therapeutic sensitivity between molecular subtypes.

Our results suggest that the molecular subtypes we constructed have potential application value in the prognosis evaluation and treatment guidance of AML patients.