A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects

Abstract

Is it possible to have an available vaccine that eradicates cancer? Starting from this question, this article tries to verify the state of the art, proposing a different approach to the issue. The variety of cancers and different and often unknown causes of cancer impede, except in some cited cases, the creation of a classical vaccine directed at the causative agent. The efforts of the scientific community are oriented toward stimulating the immune systems of patients, thereby preventing immune evasion, and heightening chemotherapeutic agents effects against cancer. However, the results are not decisive, because without any warning signs, metastasis often occurs. The purpose of this paper is to elaborate on a vaccine that must be administered to a patient in order to prevent metastasis; metastasis is an event that leads to death, and thus, preventing it could transform cancer into a chronic disease. We underline the fact that the field has not been studied in depth, and that the complexity of metastatic processes should not be underestimated. Then, with the aim of identifying the target of a cancer vaccine, we draw attention to the presence of the paradoxical actions of different mechanisms, pathways, molecules, and immune and non-immune cells characteristic of the tumor microenvironment at the primary site and pre-metastatic niche in order to exclude possible vaccine candidates that have opposite effects/behaviors; after a meticulous evaluation, we propose possible targets to develop a metastasis-targeting vaccine. We conclude that a change in the current concept of a cancer vaccine is needed, and the efforts of the scientific community should be redirected toward a metastasis-targeting vaccine, with the increasing hope of eradicating cancer.

Keywords: TGF-β; cancer-associated fibroblasts; epithelial–mesenchymal transition; immune cells; immunotherapy; metastasis; paradoxical results; tumor microenvironment; tumor-associated macrophages; vaccines.

Figure 1

Paradoxical concepts about intrinsic cells and mediators within the TME. Normoxia/hypoxia. LOX, an enzyme that determines ECM remodeling and promotes cancer cell invasion, is promoted in the lung by high oxygen concentrations, while in other organs, it is induced by hypoxia through HIF-1 ROS. Oxidative stress is a well-known cancer inducer and can activate both EMT and MET; however, it can act as an oncosuppressor, promoting ferroptosis and preventing tumor metastasis. Metabolism. While the primary site is usually glycolytic (via the Warburg effect), during EMT, oxidative phosphorylation prevails; glutamine uptake, instead of glucose, has been revealed in brain metastases from breast cancer. GJIC. GJs mediating cell–cell communication are tumor suppressors in the early phases of carcinogenesis, but they are pro-metastatic in later phases, participating in the formation of the pre-metastatic niche. EMT-FTs. Twist1 and ZEB1 were found to be overexpressed and downregulated, respectively, in lung cancer. A switch from ZEB2 to ZEB1 promotes the progression of melanoma, suggesting that these two ZEB proteins function in an opposite manner and that ZEB1 acts paradoxically. PRRX1 overexpression is associated with a favorable prognosis in breast cancer patients, but its upregulation is related to a poor prognosis linked to increased EMT in colorectal cancer. The excessive formation of filamentous actin (F-actin) determines YAP stabilization, favoring liver metastasis. On the other hand, YAP can both increase and reduce the formation of F-actin, thus making YAP a likely oncosuppressor as well. Hh was verified to have a tumor-promoting effect on breast and cervical cancers and to inhibit EMT; however, a tumor-suppressive effect was shown in pancreatic cancer. FOXO factors have distinct effects on cancer: while FOXO1 can promote EMT and metastasis in breast cancer, FOXO3a represses EMT in prostate cancer. Other details and references can be found in the text. EMT: epithelial–mesenchymal transition; EMT-TFs: EMT transcription factors; GJIC: gap junction intercellular communication; Hh: hedgehog; LOX: lysyl oxidase; MET: mesenchymal–epithelial transition; ROS: reactive oxygen species.

Figure 2

Paradoxical concepts about extrinsic cells and mediators within the TME. Cytokines/chemokines. Type I IFNs can inhibit the pre-metastatic niche by increasing neutrophil cytotoxicity in cancer cells and, in later stages of carcinogenesis, act as immunosuppressors, as well as EMT and inflammation inducers. Chemokines have both proangiogenic (mainly CXCR2) and anti-angiogenic (mainly CXCR3) effects. CAFs. In the presence of CAV-1, CAFs result in tumor growth via host–parasite association; in its absence, they secrete high levels of TGF-β, inducing EMT and metastasization. However, TGF-β can act as an oncosuppressor in early phases by inducing lethal EMT and apoptosis. Crosstalk between CAFs and cancer cells is mediated by CAF-derived TGF-β, which induces some cancer hallmarks (inflammation, growth, migration, and invasion), and conversely, tumor cells can induce NF transformation into CAFs through Smad and NF-κB signaling. Crosstalk between CAFs and immune cells also occurs through Smad and NF-κB signals, leading to immunosuppression. TAMs are switched from antitumoral M1 (in normoxia) to protumoral M2 (in hypoxia), and MDSCs are recruited. Tregs can have opposite effects: they can have protumoral effects by means of neutrophils and macrophages (Mø) and antitumoral effects by activating antigen-presenting cells (APCs), such as dendritic cells (DCs) and cytotoxic T cells (CTLs). Neutrophils can also act in a bimodal way: they are antitumoral in the absence of TGF-β and protumoral in its presence via undergoing NETosis (which entraps cancer cells in tumoral vessels). More details and references can be found in the text. CAFs: cancer-associated fibroblasts; CAV-1: caveolin-1; EMT: epithelial–mesenchymal transition; IFN: interferon; NET: neutrophil extracellular traps; NFs: normal fibroblasts; TAMs: tumor-associated macrophages.

Figure 3

A schematic view of the contrasting roles of inflammation/immune responses during cancer progression. At tumor onset, a pro-inflammatory reaction prevails (left side), with DCs inducing Th1 cell polarization, with either direct or indirect antitumoral effects through the activation of CTLs and NK cells and the polarization of TAMs to the M1 type. During tumor progression, however, chronic inflammation occurs (right side), whereby tumor growth is promoted by Th2 CD4+ T cells and MDCS, which, in combination, both repress CD8+ cytotoxicity and induce the protumoral polarization of the innate immune response (such as M2 polarization of TAMs) via cytokine secretion (IL-4, IL-10, and IL-13). Treg cells have a dual role (yin and yang) in that, depending on the context, they have either antitumoral or protumoral effects via the secretion of IL-10 and TGFβ. On the other hand, cancer cells produce TGF-β, which can have protumoral or antitumoral Treg-mediated effects. Type I IFNs can activate antitumoral effects by autoregulating DCs and increasing the functions of T cells; however, chronic exposure to these cytokines has opposite effects. Different chemokines also have opposite effects on tumoral angiogenesis. CTL: cytotoxic lymphocyte; DCs: dendritic cells; IFN I: type 1 interferon; MDSC: myeloid-derived suppressor cell; NK: natural killer; TAM: tumor-associated macrophage: Treg: regulatory T cell.