Potential Effects of Regulating Intestinal Flora on Immunotherapy for Liver Cancer

Abstract

The intestinal flora plays an important role in the occurrence and development of liver cancer, affecting the efficacy and side effects of conventional antitumor therapy. Recently, immunotherapy for liver cancer has been a palliative treatment for patients with advanced liver cancer lacking surgical indications. Representative drugs include immune checkpoint inhibitors, regulators, tumor vaccines, and cellular immunotherapies. The effects of immunotherapy on liver cancer vary because of the heterogeneity of the tumors. Intestinal flora can affect the efficacy and side effects of immunotherapy for liver cancer by regulating host immunity. Therefore, applying probiotics, prebiotics, antibiotics, and fecal transplantation to interfere with the intestinal flora is expected to become an important means of assisting immunotherapy for liver cancer. This article reviews publications that discuss the relationship between intestinal flora and immunotherapy for liver cancer and further clarifies the potential relationship between intestinal flora and immunotherapy for liver cancer.

Keywords: adjuvant therapy of immunity; checkpoint inhibitors for intestinal flora; liver cancer immunotherapy.

Figure 1

Gut microbiota directly stimulates the antitumor T-cell response. (A) Helicobacter hepaticus directly stimulates RORγtFOXP3 to regulate T cells to selectively inhibit TH17 cells. (B) Akkermansia muciniphila stimulates antigen-specific T cells and B cells to produce IgG1 antibodies, which can regulate PD-1 checkpoints and enhance antitumor effects. (C) Fragile bacilli and components directly or indirectly stimulate macrophages, activate STING to produce interferon, and can enhance the efficacy of CTLA-4 treatment. (D) Bifidobacterium can directly act on macrophages; activate STING and IFN; produce IFN1, IFNγ, TNF-α, and IL-2; enhance CD8+ T cell expression; upregulate PD-L1 expression on the tumor cell surface; enhance antibody CD47 expression; and inhibit the growth of mouse tumor cells. (E) Bacterial flagellar proteins can directly stimulate the expression of TLR5 and TLR4 on the surface of DCs and macrophages; act on T cells; produce IFNα, IL-8, and IL-6; enhance the host immune response; and inhibit tumor cell growth.

Figure 2

Intestinal microbiota initiates cross-antitumor T-cell responses by forming a shared antigenic mimic with tumor cells. (A) The SVYRYYGL (SVY) on the surface of Bifidobacterium breve cross-reacts with the mouse tumor model neoantigen SIYRYYGL (SIY). Bifidobacterium promotes the expression of SVY-responsive T cells, acts on the SIY on the surface of tumor cells, enhances the expression of CD8+ T cells, and inhibits the killing of tumor cells. (B) The Enterococcus hirae bacteriophage has a common antigen, TMP, with the tumor cell surface antigen, which triggers a crossover antitumor T-cell response, enhances CD8+ T-cell expression, and enhances the efficacy of PD-1 blockers. (C) The FAP2 protein of Fusobacterium nucleatum interacts with the inhibitory T-cell receptor TIGIT, which can directly inhibit the expression of NK cells and T cells, thereby inhibiting the immune response of antitumor cells.

Figure 3

Inosine-modulated antitumor immunotherapy.

Figure 4

Bile acid-regulated antitumor immunotherapy.

Figure 5

Short-chain fatty acids modulate antitumor immunotherapy.