Gut Microbiota: A Promising Milestone in Enhancing the Efficacy of PD1/PD-L1 Blockade Therapy

Abstract

In the past few decades, immunotherapy has emerged as one of the most promising strategies among current treatments of cancer. In particular, the field of PD1/PD-L1 inhibitors has been boosted, widely applied into clinical practice with potent therapeutic efficacy and remarkable survival benefits on various cancers such as melanoma, non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC). However, the application of PD1/PD-L1 blockade therapy is still quite restricted because of unexpected toxicities, limited response rate, as well as associated resistance. In consequence, searching for potential strategies that possibly resolve the existing limitations and enhance the therapeutic responsiveness of PD1/PD-L1 blockade is of great significance. Fortunately, the gut microbiome has been demonstrated to serve as a pivotal regulator in anti-PD1/PD-L1 therapy, providing an applicable tool to improve anti-PD1/PD-L1 clinical efficacy. In this review, we summarized published advancements about how microbiota modulated in anti-PD1/PD-L1 therapy and illustrated its underlying mechanisms, giving insights into putative manipulation of gut microbiota to facilitate PD1/PD-L1 blockade.

Keywords: PD1/PD-L1; cancer; gut microbiome; immunotherapy; probiotics.

Figure 1

Putative mechanisms concerning the role of the gut microbiome in anti-PD1/PD-L1 immunotherapy. (A) In preclinical murine models, the abundance of Bifidobacterium spp./Enterococcus faecium etc. was shown to increase the cytotoxic T cell function in cancerous sites to facilitate tumor killing. (B) The enrichment of Akkermansiacea muciniphila in anti-PD-L1 responders is correlated with enhanced dendritic cells (DCs) activation, thus provoking IL-12 secretion, promoting the trafficking of CD4⁺ CCR9⁺ memory T cell and CD4⁺ CXCR3⁺ T cells from mesentery lymph nodes (mLNs) to tumor draining lymph nodes (dLNs), ultimately enhancing anti-tumor effect by motivating effector T cells. (C) Ruminococcaceae/Clostridales/Feacalibacterium in the GI tract mediate in anti-tumor effect via enhancing the ratio of CD4⁺ and CD8⁺ T cell ratio while downregulating the activity of regulatory T cells and myeloid derived suppressor cells (MDSCs). (D) Bacteria themselves and associated metabolites are also potential regulators in anti-PD1/PD-L1 therapy, primarily via driving Th1 cell differentiation peripherally, potentiating DCs function as well as diminishing circulating regulatory T cells (T_regs), thus ameliorating immunosuppression and reinforcing immune activation.