Research and application of hydrostatic high pressure in tumor vaccines (Review)

Abstract

It is well known that hydrostatic pressure (HP) is a physical parameter that is now regarded as an important variable for life. High hydrostatic pressure (HHP) technology has influenced biological systems for more than 100 years. Food and bioscience researchers have shown great interest in HHP technology over the past few decades. The development of knowledge related to this area can better facilitate the application of HHP in the life sciences. Furthermore, new applications for HHP may come from these current studies, particularly in tumor vaccines. Currently, cancer recurrence and metastasis continue to pose a serious threat to human health. The limited efficacy of conventional treatments has led to the need for breakthroughs in immunotherapy and other related areas. Research into tumor vaccines is providing new insights for cancer treatment. The purpose of this review is to present the main findings reported thus far in the relevant scientific literature, focusing on knowledge related to HHP technology and tumor vaccines, and to demonstrate the potential of applying HHP technology to tumor vaccine development.

Keywords: hydrostatic high pressure; tumor vaccine; immunogenic cell death; dendritic cell; Annexin A5.

Figure 1.

Characterization of HHP treatment and its effects on tumor cells. HHP treatment effectively induces tumor cell killing and is considered a novel method for the preparation of autologous tumor cell vaccines from the tumor tissue obtained from biopsies or surgery. ATP, adenosine triphosphate; CALR, calreticulin; ER, endoplasmic reticulum; HHP, high hydrostatic pressure; HMGB-1, high mobility group box 1; HSP, heat shock protein.

Figure 2.

(A) HHP reduces the ability for growth, DNA replication, RNA transcription, protein synthesis, and survival. The arrows show the highest limits of these capacities. (B) Schematic image of the effect of the pressure treatment on the process of cell killing. At HHP below 200 MPa, the treated cells have adhered. When cells are treated with HHP above 200 MPa, the high pressure induces increased cell permeability, cell inactivation, and leads to cell killing. HHP, high hydrostatic pressure; MPa, megapascal.

Figure 3.

Manufacturing of the DC-based vaccine using immunogenic HHP-treated cancer cells. The live cancer cells are treated with HHP treatment. Then, cancer cells are cultured for a few hours to expose relevant immunogenic molecules on the treated cell surfaces (HSP70/90 and CALR) or released into the vicinity of dying cells (ATP and HMGB1). HHP-treated cancer cells are loaded to DCs, which are made from mononuclear cells obtained from patients. DCs generated from pulses of cancer cells treated with HHP can mature. DCs acquire the stimulatory phenotype with the high expression of costimulatory molecules (CD80, CD83, CD86), MHC class II molecules, and with the production of proinflammatory cytokines (IL-1β, IL-6, IL-12) and the mediators such as NO. Anti-inflammatory cytokines such as IL-10 are produced in lower amounts. Some doses of the DC-based vaccines are prepared, cryopreserved, and administered back to the patients in the course of therapy. ATP, adenosine triphosphate; CALR, calreticulin; DC, dendritic cell; HHP, high hydrostatic pressure; HMGB1, high mobility group box 1; HSP, heat shock protein; IL, interleukin; MHC, major histocompatibility complex; NO, nitric oxide.

Figure 4.

DC-mediated immune responses against cancer induced by dead cancer cells and the adjuvant AnxA5. Apoptotic and necrotic tumor cells resulting from treatment as well as from in vitro inactivation interact with immune cells of the innate (macrophages) and adaptive (DC) immune system. The swift clearance of apoptotic cells leads to anti-inflammatory or non-inflammatory responses. The clearance of apoptotic cancer cells by macrophages can be blocked by AnxA5, resulting in abundant secondary necrosis. The necrotic cells can release DAMPs, such as HMGB1 or HSP70, which are danger signals. Stimulation of danger signals and uptake and presentation of dead cancer cell-derived antigens by DCs leads to the specific antitumor immunity. Danger signals may also directly activate cells of the innate immune system. The ‘eat me’ signals of early apoptotic cells can promote the phagocytosis of dying cancer cells by DCs. AnxA5, Annexin A5; DAMPs, damage-associated molecular patterns; DC, dendritic cell; HMGB1, high mobility group box 1; HSP70, heat shock protein 70.

Figure 5.

Standard tumor therapy combines with immune therapy and act together in the elimination of tumors. In vivo, therapy-induced cancer cell death by RT and CT can be more immunogenic using the immune-stimulatory adjuvant AnxA5. HHP-treated tumor cells can be incubated with recombinant AnxA5 to further enhance the immunogenicity before reinjection into patients. AnxA5 may also increase the immunogenicity of malignant cells prepared from the primary tumor for vaccination purposes. Complete cancer cell killing by preserving the immunogenicity can be achieved by the inactivation of autologous cancer cells with HHP. The injection of AnxA5 can modulate the anticancer response of dead cancer cells induced by RT and CT treatment. The results reveal that the growth of the syngeneic tumors is not only inhibited by RT but also solely by treatment with AnxA5. AnxA5, Annexin A5; CT, chemotherapy; HHP, high hydrostatic pressure; RT, radiotherapy.