Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid progenitor cells. Recently, in a research report entitled "STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance" published in the international journal Frontiers in Immunology, scientists from Karl-Landsteiner University of Health Sciences in Austria and other institutions found that STAT3 protein may help the immune system identify leukemia cells. The relevant research results are very important for the development of new immunotherapies in the future.
The results of this study show that STAT3 affects the formation of surface structures of leukemia cells, making them more susceptible to the immune system. If these structures are missing, leukemia cells can escape the body's innate immune surveillance. The expression of STAT3 in leukemia cells and on surface structures may serve as a potential biomarker for future immunotherapy. AML is the second most common type of leukemia in children and the most common leukemia in people over 50 years old. Although patients have good treatment options, nearly half of AML patients will experience disease relapse.
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Immunotherapy helps the body's immune system fight residual cancer cells and is seen as a promising approach to improve patients' relapse rates. Many clinical trials focus on natural killer cells (NK cells), lymphocytes that can kill virus-infected cells and tumor cells. However, AML cells often evade the host's immune defense mechanisms, and understanding the underlying mechanisms is crucial to the success of immunotherapy. Researcher Professor Dagmar Stoiber-Sakaguchi said, "For the first time, we have revealed how STAT3 improves the elimination of leukemia cells by NK cells, perhaps due to its interaction with ICAM-1, a surface structure on AML cells." In fact, the researchers also found that AML cells without STAT3 were less efficiently eliminated by NK cells and carried less ICAM-1.
Figure 1. STAT3-deficient AML cells show reduced expression of ICAM-1. (Witalisz-Siepracka A, et al. 2024)
ICAM-1 (Intercellular Adhesion Molecule 1) serves as a binding site for patrolling NK cells and is also important for the destruction of cancer cells. If the level of ICAM-1 is low, NK cells cannot work properly. In detail, NK cells can form so-called immunological synapses with ICAM-1 on leukemia cells. Cytotoxic molecules can then be transferred to AML cells via these connections and cause cancer cell death. The researchers point out that without STAT3, this process cannot take place effectively, which may help AML cells to evade the host's immune defenses.
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To verify the researchers' findings, they modified AML cells that lack STAT3 so that they produce ICAM-1 in the absence of STAT3, suggesting that the effects of the lack of STAT3 (which NK cells cannot effectively eliminate) may be compensated. Now there is a clear indication that STAT3 binds to ICAM-1 and thus makes leukemia cells more susceptible to the host's immune system. After further analysis, the researchers found that the expression of STAT3 and ICAM-1 in leukemia cells of AML patients was positively correlated, that is, the more STAT3 was synthesized, the more ICAM-1 could be produced in the cells.
The researchers said that patients with higher levels of ICAM-1 expression in their bodies tended to survive longer. This may be because NK cells can more effectively eliminate AML cells. The expression of STAT3/ICAM-1 may serve as a potential biomarker for the development of new individual immunotherapies in the future. In summary, the results of this study reveal a new role played by STAT3 in preventing AML cells from escaping NK cell surveillance, and emphasize that the STAT3/ICAM-1 axis may serve as a new potential biomarker for NK cell therapy in AML.
Reference
Witalisz-Siepracka A, et al. STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance. Frontiers in Immunology, 2024, 15: 1374068.