Gut microbiota: impacts on gastrointestinal cancer immunotherapy

Abstract

The association of gut microbiota with gastrointestinal carcinogenesis has been heavily investigated since the recent advance in sequencing technology. Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression. Given by its importance, emerging studies have focussed on targeting microbiota to ameliorate therapeutic effectiveness. It is now clear that the microbial community is closely related to the efficacy of chemotherapy, while the correlation of microbiota with immunotherapy is much less studied. Herein, we review the up-to-date findings on the influence of gut microbiota on three common immunotherapies including adoptive cell transfer, immune checkpoint blockade, and CpG-oligodeoxynucleotide therapy. We then explore three microbiota-targeted strategies that may improve treatment efficacy, involving dietary intervention, probiotics supplementation, and fecal microbiota transplantation.

Keywords: CpG-oligodeoxynucleotide therapy; Gut microbiota; adoptive cell transfer; blockade-induced adverse events; fecal microbiota transplantation; gastrointestinal cancer; immune checkpoint blockade; probiotics.

Figure 1.

Gut dysbiosis interacts with host immunity to induce chronic inflammation. Blue and red rods represent beneficial commensals and pathobionts respectively. TLR4 from innate immunity recognizes MAMPs (e.g. LPS, flagellins) of dysbiotic microbiota and leads to initiation of NF-κB-dependent downstream production of pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-17, IL-23). The NF-κB signaling cascade can also be activated by microbial derivatives especially a group of metabolites known as bile acid. In addition, dysbiosis can increase gut barrier permeability to induce translocation of pathobionts and metabolites from the mucosa to bloodstream, and eventually into the hepatopancreatic ductal system. All these processes can cause persistent inflammation, which can further exaggerate the imbalanced microbial community, thus forming a vicious cycle and promoting carcinogenesis

Figure 2.

Targeting gut microbiota as adjuvants of cancer immunotherapy. Dietary intervention, probiotics and FMT are microbiota-targeted strategies that can ameliorate the efficacy of immunotherapy in 4 distinct mechanisms. a | As the microbiota composition is easily affected, utilizing these extrinsic strategies can restore the imbalanced microbial community to alleviate dysbiosis-associated pathology. b | The anticancer immunity in tumor microenvironment is inhibited to flavor tumor cell growth. By reconstructing the T cell repertoire, the suppressed host immunity can be provoked once again to fight against cancer. c | A diversity of immune cells (e.g. NK and dendritic cells) infiltrate from the circulation into the tumor to further contribute to killing of cancer cells. d | Apart from direct effects on the tumor, the anticancer immunity is stimulated by these strategies to increase or decrease production of anti-inflammatory or pro-inflammatory cytokines respectively, thereby alleviating persistent inflammation in cancer patients