Design Strategy for Breast Cancer Vaccine: Comparison
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Breast cancer has been recorded as the type of cancer that causes the highest mortality in women due to its high incidence. Given the devastating implications of the disease and the growing number of cases, many scientists and research organizations have dedicated their efforts to the fight against breast cancer. Vaccines are an upcoming medical intervention for breast cancer. By targeting the tumor antigen, cancer vaccines can be designed to train the immune system to recognize tumor cells.

  • breast cancer
  • immunoinformatics
  • vaccine
  • epitope

1. Introduction

According to the Global Cancer Observatory in 2020, around 11.7% of new worldwide cases of cancer are breast cancer. Approximately 6.9% of deaths by cancer were caused by breast cancer in 2020 all around the world [1]. In Indonesia, 19.2% of cancer cases are breast cancer, making it the most prevalent cancer [2]. Breast cancer has been recorded as the type of cancer that causes the highest mortality in women due to its high incidence. Given the devastating implications of the disease and the growing number of cases, many scientists and research organizations have dedicated their efforts to the fight against breast cancer [3]. Several suggestions, such as living a healthy lifestyle, getting regular exercise, managing body weight, and quitting smoking, should be taken into consideration as preventative measures. Many healthcare organizations advise annual and routine mammography after the age of 40 for early disease identification. As a result, the sickness would be diagnosed early, and the therapy would begin before it spread to other bodily areas. There are currently three ways to treat breast cancer: surgical ablation, radiotherapy, and chemotherapy. Each of these treatments can have bad side effects or even cause the cancer to reoccur [4]. Many laboratories are working on breast cancer vaccines to generate a long-lasting anticancer response with few side effects.
Contrary to the traditional idea of immunizing against infectious diseases only, the concept of vaccines can be adopted for both cancer prevention and therapy. A cancer vaccine can theoretically treat the malignancy by inducing T cell anti-tumor mechanisms. It causes minimal effects compared to conventional cancer therapy. Radiotherapy, chemotherapy, and endocrine therapies can cause adverse effects such as skin toxicity, peripheral neuropathy, hair loss, infertility, impaired cognitive function, and tiredness [5]. However, creating a cancer vaccine has proven to be difficult, partly because there are so many possible antigens that the immune system could attack. Many of these antigens may also develop before, during, or after the neoplastic process. Despite optimistic advancements in cancer immunotherapy, the search for vaccine target identification techniques continues to this day.
Though there is no widely accepted universal technique or instrument for rationally creating vaccines, researchers agree on various steps needed during the design process. Computational methods can be used to significantly reduce the time and cost of developing vaccines by mapping thousands of biological components in silico. Recent studies have highlighted the influence of these techniques on vaccine design from a variety of perspectives, including proteome retrieval, epitope prediction, epitope selection, molecular interaction, and immune response simulation [6][7][8]. This set of techniques to select potential vaccine targets and simulate immune responses is often referred to as immunoinformatics.
The immunoinformatics approach to vaccine design relies heavily on antigen identification and the selection of epitopes that can induce an immune response. With various optimized algorithms and high-throughput genomics analysis, antigen search, molecular docking, and model simulations to predict immune responses can be carried out more quickly. This will of course reduce the intensity of testing work in the laboratory [9].

2. Design Strategy for Breast Cancer Vaccine

Cancer vaccines are now focusing on subunit components rather than cell-based or virus-based vaccines [10]. The immunogenicity of peptide-based vaccinations is low due to the limitations of human leukocyte antigen (HLA) polymorphism and the tiny size of antigen epitopes themselves. It is frequently difficult to elicit a strong immunological response, which leads to immune tolerance. Adjuvants are used in conjunction with peptide-based vaccinations to improve the overall immune response. Not all protein antigen sites are similarly immunogenic to B and T cells. Instead of inactivated tumor cells, peptide-based vaccines target key neutralizing epitopes to get a more targeted immune response [11]. Cancer vaccines based on peptides often require both CD8+ T cell epitopes and CD4+ T cell epitopes. CD8+ T cell epitopes activate CTLs’ tumor immunity via the antigen cross-presentation pathway, whereas CD4+ T cells stimulate helper T cells to keep CTLs functional [12]. The length of the peptide chain has a significant impact on the performance of the peptide vaccination. CD8+ T cell epitopes are typically short peptides with a short half-life in vivo. This peptide is directly applied to the HLA-I molecules of APCs or other nucleus cells, removing the need for processing in specialized APCs. CTL activation is limited by the lack of costimulatory molecules, which are needed for CD8+ T cells to work well [13]. As a result, short peptides frequently activate CTLs and even induce CTL tolerance [14]. Furthermore, shorter peptides are often constrained by HLA types. Long peptides, as opposed to short peptides, enable greater coverage of HLA, encompassing many epitopes while also supporting motif recognition and binding to increase immunogenicity. Long peptides must be processed by APCs before being loaded directly onto HLA molecules [15]. A portion of the lengthy peptides is digested by the endosomal route after internalization, loaded onto HLA-II molecules, and identified by CD4+ T helper cells. The remaining portions enter the cytoplasmic or vacuolar route and are presented to CD8+ T lymphocytes via HLA-I molecules [16]. Long peptide vaccines have a greater chance of eliciting long-lasting and effective anti-tumor activity responses. Short peptides are often created via chemical synthesis, but lengthy peptides are generally created using protein expression systems. Immunogenicity differs among recombinant protein subunit vaccines depending on the expression platform. Cancer vaccines have been produced using a variety of expression platforms, including Escherichia coli (E. coli) [17], plants [18], yeasts [19], insect cells [20], and mammalian cells [21]. Mammalian cell proteins are the most similar to natural tumor antigens. These contents will focus on two types of antigens, tumor-associated antigens and tumor-specific antigens. Both types of antigens can be targeted in breast cancer vaccine design with several limitations. (a) Tumor-Associated Antigens (TAA) Tumor-associated antigens are molecules derived from unmutated proteins and are recognized by TCRs. They are associated with tumor cells because tumor cells produce them at significantly high levels. TAAs are useful for producing a single vaccination that can be made in huge quantities and disseminated to many patients as a one-for-all strategy. One of the most difficult issues is ensuring that TAAs elicit the optimal immune response. The immune system is meticulously calibrated to ensure that it does not harm the body. When this calibration fails, autoimmune disorders develop. Some TAAs may be detected in healthy tissues, but at low levels. As a result, tumor-associated antigens may not elicit an immunological response because the immune system regards them as foreign. On the other hand, TAAs may evade human immune tolerance systems. This could cause immune cells to target other sections of the body, potentially resulting in toxicity and safety concerns [22]. Currently, there are several peptide vaccines for breast cancer that are being developed based on TAAs such as E75 [23], GP2 [24], and AE37 [25]. (b) Tumor-Specific Antigens (TSA) Tumor-specific antigens, also known as neoantigens, are a repertoire of peptides presented on tumor cells that may be selectively recognized by neoantigen-specific T cell receptors (TCRs) in the context of human leukocyte antigen (HLA) molecules [26][27][28]. Tumor neoantigen is an aberrant protein that is completely missing from normal human organs/tissues. Tumor neoantigens can arise from a range of nonsynonymous genetic modifications, including single-nucleotide variations (SNVs), insertions and deletions (indel), gene fusions, frameshift mutations, and structural variants (SVs) [26]. The main constraint of cancer vaccines based on altered neoantigens is that they are strictly personalized, and their discovery necessitates a combination of high-throughput genomics, proteomics, and immunomics screening technologies that are presently not applicable on a broad scale. Furthermore, the success of such a highly customized strategy may be hampered by tumors’ rapid mutational rate, which leads to the continual creation of new target mutated neoantigens and, as a result, cancer immune evasion.

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