ANTICANCER EFFECTS OF AK4 IN MACROPHAGES AND T-LYMPHOCYTES

Abstract

Despite multiple therapies, including chemotherapy and immunotherapy, cancer-related mortality is still extremely high. Resistance to treatment and relapse are the two most common reasons (Yang et al., 2022). Immunotherapy is a promising method in cancer therapy. There are new forms of immunotherapy, such as CAR-T cell therapy, have use patient cells, taken, isolated, and genetically modified. The genetic modification allows T-cells to identify cancer cells and destroy them in the body (Niu et al., 2024). The new forms of immunotherapy have a proven track record in the treatment of cancer disease, most notably hematological malignancies. For example, in leukemias and B-cell lymphomas, CAR-T cell therapy has demonstrated a tremendous response (Maude et al., 2018). However, the application of this method of therapy is fraught with challenges against solid tumors due to their heterogeneity and immunosuppressive properties within the tumor microenvironment (Wang et al., 2023). The macrophage is an immune cell, and its main function is to eliminate an organism's defenses against a variety of infections by acting via phagocytosis (Chin et al., 2021). Macrophages are polarized into two categories, M1 are pro-inflammatory and activated by interferon-gamma, which stimulate the release of cytokines and inflammation (Wujak et al., 2021), M2 is an anti-inflammatory macrophage activated by IL-2, and restores tissue as a major function. Multiple studies have examined tumor-associated macrophages (TAM), the greatest population of macrophages represents our cancer microenvironment, and contributes in two ways to tumor progression and metastasis by secreting growth factors (VEGR, EGF, etc.) and secreting immunosuppression cytokines - TGF-B (Wang & Joyce, 2010). Also, tumor-associated macrophages will express the ligand as the receptor to bind with the PD-1 receptor (programmed cell death receptor) as a means to induce T-cell exhaustion. The overexpression of AK4 affects the functional activity of macrophages, especially the M1 pro-inflammatory activity. The data supports that AK4 increased more in the M1 type compared to the M2 type of macrophage. Thus, overexpression of AK4 is related to an inflammatory response (Chin et al., 2021). Therefore, in this regard, we view AK4 not only as a regulator of metabolism and inflammation, but also potential therapeutic target for developing better CAR-M therapies for the immunotherapy of solid tumors.