Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 236-244 http://medscipublisher.com/index.php/cge 240 tumor immune microenvironment (TIME). Case analyses from lung cancer and other solid tumors have shown that there is often a considerable infiltration of regulatory T cells (Tregs) and M2-type macrophages in the tumor tissues of such patients (Andersen et al., 2021). These inhibitory immune cells weaken the function of cytotoxic T cells, helping tumors evade immune clearance and providing conditions for rapid regrowth. In addition, genetic testing has found that some genes and signaling pathways related to immunosuppression and tumor progression are more active in patients with early recurrence (Wang et al., 2021). Spatial analysis also found that in patients with early recurrence, Tregs and macrophages, etc. were often closer to tumor cells. This adjacent distribution enhanced their inhibitory effect and weakened the body's ability to fight tumors (Andersen et al., 2021). This immune characteristic is significantly different from that of patients who relapse much later, indicating that the difference in TIME directly affects the timing of relapse. 5.2 Differences in the immune microenvironment of patients with advanced recurrence Conversely, patients with later recurrence usually have more cytotoxic T cells and memory T cells, and the composition of immune cells is also more balanced (Zhao et al., 2024). The number of CD8+T cells and dendritic cells in the tumors of these patients is often greater, which helps the immune system to monitor and delay tumor recurrence more effectively. In the TIME of late recurrence, inhibitory cells are less dominant. Spatial analysis shows that there are more types of immune cells and more active interactions, which may explain why they have longer recurrence intervals (Figure 2) (Maus et al., 2022). Figure 2 Phenotypic composition of cell-centered neighborhoods differs based on index cell and clinical recurrence status (Adopted from Maus et al., 2022) Image caption: (A) Illustration and visualization of all TCCN and CTCN with at least one immune cell (TCCN) or tumor cell (CTCN) present in tumor FOVs; In TCCN, index (center) tumor cell is indicated in blue, in CTCN index CTL is indicated in green, tumor cell neighbors are brown, immune cell neighbors are magenta; (TCCN n=983,823 and CTCN n=37,402) (B) Box plot comparing neighborhood frequencies of immune composition between patients based on recurrence status; Distribution of patients displayed on box plot as green circles (no recurrence) and red triangles (recurrence); (C) Distribution of tumor cell counts in TCCN and CTCN in patient cohorts; Acronyms are as follows B cells (BC), Cytotoxic T cell (CTC), Dendritic cells (DC), Macrophages (MAC), T helper cells (THC), T regulatory cells (Treg). NS indicates no significance, * indicates p value <0.01 (Adopted from Maus et al., 2022) In addition, the expression levels of immune checkpoint molecules and inhibitory cytokines in these cases are usually low, which is conducive to stimulating a strong anti-tumor immune response. This indicates that TIME may gradually change from an inhibitory state to a responsive state after surgery, thereby affecting the time and probability of recurrence (Wang et al., 2021; Maus et al., 2022).
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