Journal of Vaccine Research 2024, Vol.14, No.5, 255-268 http://medscipublisher.com/index.php/jvr 262 PD-1 receptors on T cells, leading to T cell exhaustion and anergy. This interaction effectively "turns off" the T cells, preventing them from attacking the tumor cells (Knudson et al., 2018; Dutta et al., 2023). Furthermore, breast cancer cells can induce the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that depletes tryptophan in the tumor microenvironment, leading to T cell anergy and apoptosis (Wei and Taskén, 2022). These immune evasion strategies collectively create a hostile environment for immune cells, allowing the tumor to grow and metastasize unchecked. 5.2 Immune suppression by the tumor microenvironment The tumor microenvironment (TME) in breast cancer is a complex and dynamic milieu that plays a critical role in immune suppression. The TME consists of various cell types, including cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), all of which contribute to an immunosuppressive environment. CAFs secrete extracellular matrix components and cytokines that physically and biochemically shield the tumor from immune cell infiltration. MDSCs, on the other hand, inhibit T cell activation and proliferation through the production of reactive oxygen species (ROS) and nitric oxide (NO) (Salemme et al., 2021). Hypoxia within the TME further exacerbates immune suppression by stabilizing hypoxia-inducible factors (HIFs), which promote the expression of immunosuppressive molecules like VEGF and adenosine. These molecules not only inhibit the function of effector T cells but also attract Tregs and MDSCs to the tumor site, enhancing the immunosuppressive environment. Additionally, the TME can induce metabolic reprogramming in immune cells, leading to a state of metabolic exhaustion where immune cells are unable to function effectively (Kim and Cho, 2022). This multifaceted suppression by the TME creates significant barriers to effective immunotherapy in breast cancer. 5.3 Combining vaccines with other therapies Given the complex immune evasion and suppression mechanisms in breast cancer, combining cancer vaccines with other therapeutic modalities holds promise for enhancing anti-tumor efficacy. Cancer vaccines aim to stimulate the immune system to recognize and attack tumor cells by presenting tumor-specific antigens. However, their efficacy is often limited by the immunosuppressive TME and immune evasion strategies employed by the tumor. Combining vaccines with immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 or anti-CTLA-4 antibodies can help to overcome T cell exhaustion and enhance the immune response against the tumor (Knudson et al., 2018; Dutta et al., 2023). Additionally, combining vaccines with therapies that target the TME, such as TGF-β inhibitors or IDO inhibitors, can help to reduce the immunosuppressive environment and improve vaccine efficacy (Knudson et al., 2018). Metabolic therapies that modulate the nutrient availability in the TME can also enhance the function of effector T cells and improve the overall anti-tumor response. Furthermore, integrating cancer vaccines with conventional therapies like chemotherapy or radiation can help to release tumor antigens and enhance the immunogenicity of the tumor, providing a synergistic effect. These combination strategies hold significant potential for improving the clinical outcomes of cancer vaccines in breast cancer patients. 6 Safety and Toxicity of Long-Term Cancer Vaccination 6.1 Tolerability of cancer vaccines Cancer vaccines have shown promising results in terms of tolerability among breast cancer patients. For instance, the E75 vaccine, which targets HER2/neu, has been extensively studied in phase I/II clinical trials. These studies have demonstrated that the vaccine is generally well-tolerated, with most adverse events being of low grade. Specifically, local toxicities were predominantly grade 1 (85%) and grade 2 (15%), with no grade 3 local toxicities reported. Systemic toxicities were also mostly grade 1 (71%) and grade 2 (14%), with only a small percentage (3%) experiencing grade 3 systemic toxicities (Vreeland et al., 2011). Similarly, the nelipepimut-S (NP-S) vaccine, another HER2-targeting vaccine, was well-tolerated in phase I/II studies, with the most common adverse events being injection site reactions such as erythema, induration, and
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