Intestinal microbiota: a new force in cancer immunotherapy

Abstract

Cancer displays high levels of heterogeneity and mutation potential, and curing cancer remains a challenge that clinicians and researchers are eager to overcome. In recent years, the emergence of cancer immunotherapy has brought hope to many patients with cancer. Cancer immunotherapy reactivates the immune function of immune cells by blocking immune checkpoints, thereby restoring the anti-tumor activity of immune cells. However, immune-related adverse events are a common complication of checkpoint blockade, which might be caused by the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. In this context, the intestinal microbiota has shown great potential in the immunotherapy of cancer. The intestinal microbiota not only regulates the immune function of the body, but also optimizes the therapeutic effect of immune checkpoint inhibitors, thus reducing the occurrence of complications. Therefore, manipulating the intestinal microbiota is expected to enhance the effectiveness of immune checkpoint inhibitors and reduce adverse reactions, which will lead to new breakthroughs in immunotherapy and cancer management. Video abstract.

Keywords: CTLA-4; Cancer immunotherapy; Checkpoint; FMT; ICIs; Microbiota; PD-1; PD-L1.

Fig. 1

TLRs and NLRs effectively regulate intestinal immune function. The lack of the TLR adapter MYD88 will alter the composition of the microbiota, resulting in an increase in the amount of the mucus-associated microbiota. The lack of nucleoside-binding oligomeric domain protein 1 (NOD1) leads to an increase in the size of the of microbiota, including increased numbers of Clostridium, Bacteroides, segmented filamentous bacteria (SFB), and Enterobacteriaceae. Lack of NOD2 also leads to an increase in the size of the mucus-associated microbiota, which induces inflammation and colorectal cancer. The microbiota produce metabolites that activate NOD-, LRR-, and pyrin domain-containing 6 (NLRP6) and secretes interleukin (IL)-18, which maintains the stability of the mucus, and antimicrobial peptides. Activation of antigen-presenting cells (APCs) promotes the differentiation of CD4⁺ T cells into T helper (Th) cells and regulatory T cells (Tregs). Th cells regulate the function of the intestinal microbiota via the expression of immunoglobulin A (IgA). Furthermore, the secretion of IgA is regulated by the specific binding of PD-1 on the surface of Th cells to PD-L1 on the surface of B cells

Fig. 2

The regulation of the microbiota in adaptive immunity. Bacteroides fragilis stimulates TLR2 on CD4⁺ T cells by producing polysaccharide A (PSA), thereby enhancing the expression of Forkhead Box P3 (Foxp3), IL-10, and TGF-β. Butyrate activates Foxp3 via a G protein-coupled receptor (GPCR), induces differentiation of Tregs, and inhibits anti-tumor immune responses. Butyrate also indirectly promotes Treg differentiation by inducing IECs to secrete TGF-β. High concentrations of TGF-β inhibit the expression of IL-23R and promote the differentiation of Tregs. TGF-β also induces RORγt to be expressed together with Foxp3 in CD4⁺ T cells, which in turn inhibits RORγt, leading to differentiation of Tregs. Microbial metabolites SCFA and PSA can promote the proliferation of induced regulatory T cells (iTregs); however, too many iTregs infiltrating tumor tissue will weaken cancer immunity. PD-L1 can also promote the conversion of Tregs to iTregs by increasing the expression of Foxp3 and PTEN, or by inhibiting the Akt/mTOR pathway

Fig. 3

The mechanism of multiple intestinal microbiota in cancer immunotherapy. Bifidobacteria activates and causes DCs to secrete IFN-γ, which initiates the anti-tumor effect of CD8⁺ T cells. B. fragilis promotes Th1 recognition of tumor antigens and is capable of inducing DC maturation. In addition, B. fragilis can promote the differentiation of CD4⁺ T cells into Tregs, which further participate in anti-tumor immunity. Faecalibacterium induces DC maturation and promotes CD4⁺ T cell proliferation. A. muciniphila promotes activation of the CXCR3/CCR9 axis and participates in the migration of CD4⁺ T cells. Escherichia and Clostridium enhance the expression of CTLA-4 in Tregs, which is beneficial to tumor immunity

Fig. 4

Differences in microbial enrichment during immunotherapy. The Circos diagram illustrates the different effects of different members of the microbiota in the treatment of ICIs. Blue bands represent members of the microbiota that are enriched during the treatment of effective ICIs. Red bands represent members of the microbiota that are enriched during the treatment of ineffective ICIs. The numbers in parentheses are the source of the reference. (1) Chaput et al. [111] (2) Frankel et al. [115] (3) Gopalakrishnan et al. [123] (4) Matson et al. [122] (5) Routy et al. [155] (6) Routy et al. [113]. (7) Temraz et al. [156]