Triggering Immune System With Nanomaterials for Cancer Immunotherapy

Abstract

Cancer is a major cause of incidence rate and mortality worldwide. In recent years, cancer immunotherapy has made great progress in the preclinical and clinical treatment of advanced malignant tumors. However, cancer patients will have transient cancer suppression reaction and serious immune related adverse reactions when receiving immunotherapy. In recent years, nanoparticle-based immunotherapy, which can accurately deliver immunogens, activate antigen presenting cells (APCs) and effector cells, provides a new insight to solve the above problems. In this review, we discuss the research progress of nanomaterials in immunotherapy including nanoparticle-based delivery systems, nanoparticle-based photothermal and photodynamic immunotherapy, nanovaccines, nanoparticle-based T cell cancer immunotherapy and nanoparticle-based bacteria cancer immunotherapy. We also put forward the current challenges and prospects of immunomodulatory therapy.

Keywords: cancer immunotherapy; delivery system; nanomaterials; nanovaccines; photodynamic immunotherapy; photothermal immunotherapy.

FIGURE 1

NP-based delivery systems for cancer immunotherapy. NP (nanoparticles); ICD (immunogenic cell death); CRT (calreticulin); ATP (adenosine triphosphate); HMGB1 (high mobility group protein B1); TME (tumor microenvironment); TAM (tumor-associated macrophages). NP-based tumor targeted delivery systems deliver ICD inducing cytotoxic drugs or siRNA to tumor site, then NPs accumulate in the tumor interstitial space, further trigger ICD or change TME to induce immune response and finally lead to tumor cells death. NPs release ICD inducing cytotoxic drugs, inducing CRT translocate to cell surface, ATP release, and HMGB1 expression increase. This triggers tumor antigens process and produce cytotoxic T cells to induce tumor cells death. On the other hand, NPs delivery system could change TME through targeting TAM, immunosuppressive molecules and immunocytes respectively. Target TAM: NPs deliver drugs or siRNA to tumor cells, polarizing macrophages from M2 phenotype to M1 phenotype, and then stimulating inflammatory response, finally suppressing tumor growth. Target immunosuppressive molecules: NPs could act on TME related immunosuppressive molecules such as TGF-β and IDO, this will increase infiltration of CD8⁺ T cells and NK cells, resulting in tumor growth inhibition. Target immunocytes: NPs could directly act on immune cells such as macrophages and cytotoxic T cells and these cells will produce pro-inflammatory cytokines including IFN-γ and IL-2, leading to antitumor immune response increase to suppress tumor growth.

FIGURE 2

Schematic illustration of NPs based PTT and PDT therapy. NPs was injected to tumor, PTT and PDT convert light energy into heat energy and induce ROS with the help of excitation light and oxygen, then cell apoptosis and necrosis were occurred and finally leading to cell death. PTT and PDT have advantages including strong efficacy, minimal invasion and negligible side effects.

FIGURE 3

NPs based PTT immunotherapy together with IDO inhibition and PD-L1 blockade. Designed NPs such as PEG-rGO-FA-IDOi, Al-BSA-Ce6, CSPM@CpG, Gold nanostar-anti-PD-L1 antibodies were injected to tumor site, and then immune responses were triggered at a specific light wavelength. Tumor antigens are produced, dendritic cells are maturated into T cells, then T cells gather and infiltrate tumor site, promoting cytokines release like IL-12, TNFα and IFN-γ to increase effctor T cells proportion. NPs release IDO inhibitor, which could inhibit IDO converting tryptophan to kynurenine. This was beneficial to T cell proliferation. What’s more, NPs combined with anti-PD-L1 antibodies could induce PD-L1 blockade and then enhance immune response to kill tumor cells.

FIGURE 4

NPs based PDT immunotherapy. In the presence of specific wavelength excitation light, designed nanoparticles like HAS-MnO₂, AuNC@MnO₂ and H-MnO_2-PEG/Ce6&DOX transport oxygen into tumor or in situ generation of O₂ inside the tumor from endogenous H₂O₂ with catalysts, which improves tumor oxygenation level and changes tumor microenvironment, increases ROS levels, leading to tumor cell apoptosis and necrosis.