Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 237 progression. The engagement of PD-1 with its ligand PD-L1 inhibits T cell activity, thereby allowing tumor cells to evade immune surveillance. Studies have shown that blocking these checkpoints with antibodies can rejuvenate T cell responses and improve anti-tumor immunity (Gomez et al., 2020; Taghiloo and Asgarian-Omran, 2021). 3.1.2 Tumor antigen presentation and recognition Effective anti-tumor immunity relies on the presentation of tumor antigens by major histocompatibility complex (MHC) molecules to T cells. However, many tumors, including colon cancer, develop mechanisms to downregulate antigen presentation. This can occur through mutations in genes encoding components of the antigen presentation machinery, such as β2-microglobulin (B2M) and HLA class I molecules, or through epigenetic modifications that silence these genes. The reduced expression of MHC molecules on tumor cells leads to impaired recognition by cytotoxic T cells, thereby allowing the tumor to escape immune destruction (Grasso et al., 2018; Wang et al., 2020b). Immunocompromise, immune tolerance, or low antigen presentation capacity, contribute to tumor cells evading the immune system (Dersh et al., 2021). 3.1.3 Immune privilege Tumor cells can also evade immune surveillance by creating a local immune privilege. FAS is a member of the TNF receptor superfamily and expressed virtually in all types of cells, whereas FASL, its ligand, is selectively expressed on the surface of activated T cells and NK cells (Golstein and Griffiths, 2018). CTLs use the FAS-FASL and perforin-granzyme pathways as major effector mechanisms of cytotoxicity(Yajima et al., 2019). However, a decreased FAS and highly FASL expression level help colon cancer cells capable to evade FAS-FASL cytotoxicity of tumor-reactive CTLs (Xiao et al., 2019). 3.2 Immunosuppressive cells in TME 3.2.1 Tumor-associated macrophages and myeloid-derived suppressor cells Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are prominent components of the tumor immune microenvironment that facilitate immune evasion. TAMs can polarize into a pro-tumor M2 phenotype, which secretes anti-inflammatory cytokines and promotes tissue remodeling, angiogenesis, and immune suppression. MDSCs, on the other hand, inhibit T cell activation and proliferation through the production of reactive oxygen species (ROS) and nitric oxide (NO), as well as the depletion of essential amino acids like arginine and tryptophan (Lee et al., 2020; Tang et al., 2021). 3.2.2 Regulatory T cells and immune suppression Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, but in the context of cancer, they can suppress effective anti-tumor immune responses. Tregs accumulate in the tumor microenvironment and exert their immunosuppressive functions through the secretion of inhibitory cytokines such as TGF-β and IL-10, as well as through direct cell-cell contact-dependent mechanisms (Kang and Zappasodi, 2023; Shan et al., 2022). The presence of Tregs in tumors is often associated with poor prognosis due to their role in dampening cytotoxic T cell responses (Shibata, 2022; Tsuchiya and Shiota, 2021). 4 Therapeutic Strategies to Modulate the Immune Microenvironment 4.1 Immune checkpoint inhibitors Immune checkpoint inhibitors have emerged as a transformative approach in cancer therapy, working by blocking inhibitory pathways that restrain T cell activation and function. This leads to the reactivation of cytotoxic T cells, which can then target and destroy cancer cells. Two major classes of immune checkpoint inhibitors are PD-1/PD-L1 inhibitors and CTLA-4 inhibitors. 4.1.1 PD-1/PD-L1 inhibitors The PD-1 receptor, expressed on T cells, interacts with its ligands PD-L1 and PD-L2, which are often overexpressed on tumor cells and within the tumor microenvironment. This interaction delivers an inhibitory signal to T cells, reducing their proliferation, cytokine production, and cytotoxic activity. PD-1/PD-L1 inhibitors, such as pembrolizumab and nivolumab, block this interaction, thereby restoring T cell function and enhancing the immune response against tumor cells (Gomez et al., 2020; Kroemer and Zitvogel, 2021) .
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