Emerging role of natural products in cancer immunotherapy

Abstract

Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.

Keywords: AKT, alpha-serine/threonine-specific protein kinase; Adoptive immune-cells transfer immunotherapy; B2M, beta-2-microglobulin; BMDCs, bone marrow dendritic cells; BPS, basil polysaccharide; BTLA, B- and T-lymphocyte attenuator; CAFs, cancer-associated fibroblasts; CCL22, C–C motif chemokine 22; CIKs, cytokine-induced killer cells; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CTL, cytotoxic T cell; CTLA-4, cytotoxic T lymphocyte antigen-4; Cancer immunotherapy; Cancer vaccines; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; FDA, US Food and Drug Administration; HCC, hepatocellular carcinoma; HER-2, human epidermal growth factor receptor-2; HIF-1α, hypoxia-inducible factor-1α; HMGB1, high-mobility group box 1; HSPs, heat shock proteins; ICD, Immunogenic cell death; ICTs, immunological checkpoints; IFN-γ, interferon γ; IL-10, interleukin-10; Immuno-check points; Immunosuppressive microenvironment; LLC, Lewis lung cancer; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex class; MITF, melanogenesis associated transcription factor; MMP-9, matrix metalloprotein-9; Mcl-1, myeloid leukemia cell differentiation protein 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NKTs, natural killer T cells; NSCLC, non-small cell lung cancer; Natural products; OVA, ovalbumin; PD-1, programmed death-1; PD-L1, programmed death receptor ligand 1; PGE-2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TAMs, tumor-associated macrophages; TAP, transporters related with antigen processing; TGF-β, transforming growth factor-β; TILs, tumor infiltration lymphocytes; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; TSA, tumor specific antigens; Teffs, effective T cells; Th1, T helper type 1; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; mTOR, mechanistic target of rapamycin.

Graphical abstract

Figure 1

Cancer immunotherapies approved by the FDA.

Figure 2

Tumor-associated immunosuppressive microenvironments and immunotherapy: (A) tumor immunosuppressive microenvironment. (B) tumor associated-agents presenting process. (C) Immunological checkpoints and (D) immunosuppressive factors and cells.

Figure 3

Immunogenic cell death (ICD) effect induced by natural products. Natural products (A. Capsaicin; B. Ginsenoside Rg3; C. Resveratrol; D. Quercetin: Alantolactone=1:4; E. Shikonin) induce immunogenic cell death (ICD) effect through damage-associated molecular patterns (DAMPs), including calreticulin (CRT), heat shock proteins (HSPs), and high-mobility group box 1 (HMGB1), to increase the tumor immunogenicity and make the tumor cells into “therapeutic vaccines”.

Figure 4

Saponins improve the therapeutic effect of cancer vaccines as adjuvants.

Figure 5

Natural products improve the therapeutic effect of cancer vaccines as adjuvants. (A) Curcumin and dioscorea polysaccharides sensitize cancer vaccines by down-regulating NF-κB signaling pathway in tumor cells. (B) Polysaccharides enhance the efficiency of cancer vaccines. (C) λ-Carrageenan, rutin, and uncarinic acid C sensitive cancer vaccines through TLR4 pathway.

Figure 6

Natural products improve the therapeutic effect of cancer vaccines as adjuvants. (A) Flavonoids; (B) other natural products.

Figure 7

Natural products down-regulate the expressions of PD-1 and PD-L1.

Figure 8

Natural products combine with anti-PD-1 and anti-PD-L1 antibodies to enhance the therapeutic outcomes of these antibodies. (A) Andrographolide improve the efficiency of anti-PD-1 antibodies (CD279, BP0146) by reducing PGE2 secretion; (B)Diosgenin enhance the therapeutic outcomes of anti-PD-1 antibodies (Clone 29F.1A12) by modulating intestinal microbiota; (C) Crytotanshinone improve the efficiency of anti-PD-L1 antibodies (Clone 10F.9G2) through activation of NF-κB pathway; (D) Puerarin improve the efficiency of anti-PD-L1 antibodies through inhibiting the CAFs activities.

Figure 9

Natural products enhance the therapeutic effect of adoptive cell transfer therapy. (A) The generation of anti-tumor immune cells used for adoptive cell therapy. Reprinted with the permission from Ref. . Copyright © 2008, nature publishing group. (B) Hedyotis diffusa polysaccharides improve the efficiency of adoptive treatment of cytokine-induced killer (CIK) cells; (C) 6-gingeral expand the number of T cells in vitro for adoptive therapy; (D) neem leaf glycoprotein (NLGP) can significantly enhance the activity of immune cells in spleen; (E) Fucosylation can enhance the anti-tumor activity of T cells of adoptive therapy; (F) Curcumin improve the efficiency of adoptive T cells treatment.

Figure 10

Nano-drug delivery system design for natural products. (A) Scheme image of CUR@PPC-aPD-1. This novel nanoparticle linked anti-PD-1 antibodies on its surface through pH sensitivity linker and encapsulating curcumin. Reprinted with the permission of Ref. . Copyright © 2020, American Association for the Advancement of Science. (B) Nano-formulated codelivery of quercetin and alantolactone with DSPE-PEG2000 and TPGS. Reprinted with the permission of Ref. . Copyright © 2019, American Chemical Society. (C) Synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP) to form Ganoderma lucidum polysaccharide-conjugated bismuth sulfide nanoparticles. Reprinted with the permission of Ref. . Copyright © 2019, American Chemical Society. (D) Structure of angelica sinensis polysaccharide PLGA nanoparticles encapsulating ASP (immunopotentiator) and OVA (model protein antigen). Reprinted with the permission of Ref. . Copyright © 2018, Elsevier B.V. (E) Curcumin–polyethylene glycol conjugate (CUR–PEG), which can self-assemble to nanoparticles, showed combination effect with LCP-based peptide nanoparticles. Reprinted with the permission of Ref. . Copyright © 2016, The American Society of Gene & Cell Therapy.