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Oncology
There has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body’s natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment.
- tumor microenvironment
- cancer vaccine
- immunotherapy
- cell-based
- dendritic cell
1. Introduction
Tumor microenvironments (TMEs) involve a mixed composition of transforming immune cells, blood vessels, stromal cells, and extracellular matrix, creating tumors that are exclusive to their location and diverse in composition among individual patients [1]. The metastatic progression, along with the distinct and peculiar composition of the TME, plays the most significant role in the patient’s response to treatment [2] All components of the transforming TME determine the changes and behavior of surrounding macromolecules and tissue development, creating complicated variations in immune response and tumor behavior, like suppression or stimulation of tumor growth [1,3].
The first standardized cancer immunotherapy utilized for the treatment of malignant tumors was developed by William B. Coley in 1891. For 40 years following this discovery, the ‘Coley Toxin’, developed from Streptococcal bacteria, stimulated immune system responses and was used to treat patients with bone and soft tissue sarcomas, shrinking the tumor significantly. Since the end of Coley’s research in 1933, the study of TMEs in correlation to cancer vaccine development skyrocketed, leading to cures and positive treatment outcomes of liver cancer related to hepatitis B, cervical cancer associated with human papillomavirus, colon cancer, melanomas, and bladder cancer, to name a few [4].
Cancer vaccination, also referred to as cancer immunization or cancer immunotherapy, is a therapeutic approach aimed at activating the immune system to recognize and combat cancer cells. Its primary objective is to prevent tumor growth, recurrence, or metastasis while enhancing the immune system’s capacity to identify and eliminate cancer cells. The mechanisms of cancer vaccines involve eliciting an immune response targeting specific tumor-associated antigens (TAAs), which are proteins expressed by cancer cells. This immune response involves the activation of T cells, B cells, and other immune cells, leading to the destruction of cancer cells. Cancer vaccines can serve as preventive measures in high-risk populations, known as prophylactic vaccines, and as treatment options for individuals already diagnosed with cancer, referred to as therapeutic vaccines. By harnessing the power of the immune system, cancer vaccination holds promise in providing effective strategies for cancer prevention and treatment.
Additionally, adjuvants are essential components of cancer vaccines, as they enhance immune responses by activating innate immune pathways. Adjuvants, such as Toll-like receptor (TLR) agonists, cytokines, and immune checkpoint inhibitors, have been utilized to improve vaccine efficacy. TLR agonists, such as CpG oligodeoxynucleotides (CpG-ODNs), stimulate antigen-presenting cells (APCs) and promote antigen presentation, while immune checkpoint inhibitors block inhibitory signaling pathways, allowing sustained immune activation. These adjuvants have shown promising results in preclinical and clinical studies, contributing to the development of novel cancer vaccines. Despite the challenges of cancer vaccine development regarding efficacy, several therapeutic vaccination strategies are under development and are being evaluated in preclinical and clinical trials [5].
Despite the progress made in the field of cancer vaccines, it is important to address the limitations and potential side effects of cancer vaccines. Tumor heterogeneity, immunosuppressive TMEs, and immune tolerance mechanisms pose significant challenges for vaccine efficacy. The identification of suitable TAAs and the selection of optimal adjuvants remain critical for successful vaccine development, and the overall effectiveness of cancer vaccines may vary among different cancer types and individual patients, necessitating personalized approaches. Common side effects include injection site pain, headache, influenza-like illness, fever, nausea, diarrhea, rashes, erythema, pruritus, myalgia, and dyspnea. Serious adverse events are less common but may involve immune system disorders, psychiatric disorders, and pulmonary embolism. While rare, varying levels of toxicity have been observed in some cases. Vaccines and their adjuvants can also lead to additional complications, such as hyponatremia, liver enzyme elevation, anemia, colitis, and increased creatinine levels. Furthermore, vaccine-induced immune responses, particularly T cell responses, have the potential to cause tumor pseudo-progression, as highlighted by M. Platten et al. (2021) [6]. It is essential to carefully monitor and manage these immune-related reactions to ensure the safety and efficacy of cancer vaccines.
2. Cellular Composition of Tumor Microenvironment
Cancer vaccine therapeutics hold great promise in stimulating the immune system to target cancer cells. However, their effectiveness is influenced by the complex cellular composition of the TME. The TME encompasses immune cells such as T cells, B cells, and natural killer cells (NK), each playing distinct roles in the anti-tumor immune response. T cells exhibit phenotypic plasticity, allowing them to differentiate into effector T cells or immunosuppressive regulatory T cells (Tregs) [3,7]. Immune checkpoint receptors expressed by T cells, such as PD-1 and CTLA-4, modulate T cell activation and function. Blocking these immune checkpoint pathways has shown success in cancer immunotherapy.
B cells, on the other hand, possess multifaceted functions within the TME. They can produce antibodies, regulate antigen processing and presentation, and exhibit pro- and anti-tumorigenic properties [8]. Regulatory B cells (Bregs) secrete immunosuppressive proteins, like IL-10 and IL-35, dampening the anti-tumor immune response [1,9]. The dynamic interactions between these immune cells and the tumor cells within the TME shape the efficacy of cancer vaccines. Furthermore, the TME comprises other components, such as dendritic cells (DCs), neutrophils, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), each with distinct contributions to tumor progression and immune modulation.
While cancer vaccines hold the potential to stimulate the immune system to target cancer cells, there are limitations to their effectiveness. The TME’s immunosuppressive nature, genetic instability, and heterogeneity pose challenges to cancer vaccine therapy. Targeting specific components of the TME, such as immune checkpoints or fibroblast activation, may help overcome these limitations and enhance the effectiveness of cancer vaccines.
3. Mechanisms of Cancer Vaccines
Cancer vaccines employ various mechanisms to stimulate the immune system and generate an effective anti-tumor response. One common approach involves the use of DCs, which are potent APCs. In one method, DCs are collected from the patient’s blood or generated in the laboratory. They are then matured and activated using immune-stimulating molecules or tumor antigens. After loading the DCs with tumor-specific antigens (TSAs) derived from tumor cells or genetic material, the loaded DCs are administered back to the patient. These DCs migrate to lymphoid organs, where they interact with immune cells, such as T cells, B cells, and NK) cells. The DCs present the tumor antigens to CD4+ helper T cells and CD8+ cytotoxic T lymphocytes (CTLs), leading to their activation. The activated T cells provide help signals to other immune cells, enhancing the immune response against tumor cells. CTLs specifically recognize and target cancer cells expressing the tumor antigens, resulting in their elimination. Additionally, this vaccine aims to induce a memory response, allowing for a more effective immune response upon subsequent encounters with tumor cells.
Another strategy involves the use of whole-cell preparations derived from cancer cells. Cancer cells are collected from the patient’s tumor or established cancer cell lines. These cells are inactivated or genetically modified to reduce their ability to grow and cause disease. When administered back to the patient, the whole cells are recognized by various immune cells, including DCs, macrophages, and NK cells, triggering an immediate non-specific inflammatory response. The activated immune cells, in turn, process the tumor antigens, present them to T cells, and initiate an immune response. CD4+ helper T cells provide help signals to other immune cells, while CD8+ CTLs recognize and eliminate tumor cells expressing the presented antigens. Whole-cell cancer vaccines also aim to induce a memory response for enhanced immune protection against tumor recurrence.
Induced pluripotent stem cell (iPSC)-based cancer vaccines represent a promising approach. iPSCs are generated from somatic cells and differentiated into TME-specific cells, such as TAFs, endothelial cells, or immune cells. These iPSC-derived cells express antigens characteristic of the TME, including TSAs or molecules involved in immunosuppression. Upon administration to the patient, these cells are recognized by immune cells, leading to the activation of a robust immune response. APCs, primarily DCs, take up iPSC-derived antigens, process them, and present them to T cells. The activated T cells, particularly CD8+ CTLs, recognize and target TME components expressing TSAs. The expansion of effector cells contributes to the elimination of tumor cells, and the induction of a memory response enables a more rapid and effective immune response upon subsequent encounters with tumor cells.
In situ cancer vaccines are administered directly into the tumor site or a nearby lymph node. This approach involves the activation of APCs, such as DCs, macrophages, neutrophils, and NK cells, within the TME. The vaccine induces an inflammatory response, cytokine production, and immune cell recruitment. APC take up tumor antigens released during vaccine administration, process them, and present them to T cells. This triggers the activation of CD8+ CTLs and CD4+ helper T cells, which work synergistically to eliminate tumor cells. The activated immune cells produce effector molecules and mediate the destruction of tumor cells within the TME. In situ cancer vaccines also aim to generate a memory response for heightened protection against tumor recurrence.
Viral-based cancer vaccines utilize modified viruses to directly activate the immune response. The modified virus interacts with immune cells, including DCs, macrophages, and NK cells, triggering an inflammatory response and the release of pro-inflammatory cytokines and chemokines. The virus particles are phagocytosed by immune cells, and the TAAs expressed by the virus or delivered to infected cells are processed and presented to T cells. CD8+ CTLs recognize the presented TAAs, leading to their activation and expansion. CD4+ helper T cells provide help signals to other immune cells, and antibodies produced against the TAAs can directly bind to tumor cells, facilitating their destruction. Viral-based vaccines aim to induce a memory response, enabling a more rapid and robust immune response upon subsequent encounters with tumor cells expressing the same TAAs.
Similarly, bacteria-based cancer vaccines utilize modified bacteria to activate the immune response. The modified bacteria interact with immune cells, triggering an inflammatory response and the production of pro-inflammatory cytokines, chemokines, and other signaling molecules. APCs, particularly DCs, phagocytose the bacteria and process them, leading to the presentation of TAAs. CD8+ CTLs recognize the presented TAAs and become activated, while CD4+ helper T cells provide help signals to other immune cells. Antibodies produced against the TAAs can directly bind to tumor cells, facilitating their destruction. Bacteria-based vaccines aim to induce a memory response, leading to a more rapid and robust immune response upon subsequent encounters with tumor cells expressing the same TAAs.
Peptide cancer vaccines involve the administration of specific peptides derived from TAAs. These peptides are taken up by APCs primarily DCs, which process them and present them on their surface using major histocompatibility complex (MHC) molecules. CD8+ CTLs recognize the presented peptides on MHC class I molecules, leading to their activation and expansion. CD4+ helper T cells recognize the peptides presented on MHC class II molecules and provide help signals to other immune cells. B cells can be activated by the peptides presented by DCs, leading to the production of antibodies specific to the TAAs. The antibodies can directly bind to tumor cells, facilitating their destruction, and a memory response is induced for enhanced immune protection.
DNA and RNA cancer vaccines involve the administration of DNA or RNA molecules encoding TAAs. The administered DNA or RNA is taken up by cells, such as muscle cells or DCs, and the TAAs are produced within these cells. APCs cells, particularly DCs, take up the TAAs and present them on their surface using MHC molecules. CD8+ CTLs recognize the presented TAAs on MHC class I molecules, leading to their activation and expansion. CD4+ helper T cells recognize the TAAs presented on MHC class II molecules and provide help signals to other immune cells. B cells can be activated by the TAAs presented by DCs, leading to the production of antibodies specific to the TAAs. The antibodies can directly bind to tumor cells, facilitating their destruction, and a memory response is induced for enhanced immune protection.
Exosome-based cancer vaccines utilize exosomes loaded with TAAs or nucleic acids encoding TAAs. These exosomes are taken up by APCs cells, primarily DCs, which become activated and enhance their antigen-presenting capabilities. The TAAs delivered by exosomes are processed and presented on the surface of DCs using molecules. CD8+ CTLs recognize the presented TAAs on MHC class I molecules, leading to their activation and expansion. CD4+ helper T cells recognize the TAAs presented on MHC class II molecules and provide help signals to other immune cells. B cells can be activated by the TAAs presented by DCs, leading to the production of antibodies specific to the TAAs. The antibodies can directly bind to tumor cells, facilitating their destruction, and a memory response is induced for heightened immune protection.
This entry is adapted from the peer-reviewed paper 10.3390/cells12172159
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