Modulation of Gut Microbiota: A Novel Paradigm of Enhancing the Efficacy of Programmed Death-1 and Programmed Death Ligand-1 Blockade Therapy

Abstract

Blockade of programmed death 1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) has been used as cancer immunotherapy in recent years, with the blockade of PD-1 being more widely used than blockade of PD-L1. PD-1 and PD-L1 blockade therapy showed benefits in patients with various types of cancer; however, such beneficial effects were seen only in a subgroup of patients. Improving the efficacy of PD-1 and PD-L1 blockade therapy is clearly needed. In this review, we summarize the recent studies on the effects of gut microbiota on PD-1 and PD-L1 blockade and discuss the new perspectives on improving efficacy of PD-1 and PD-L1 blockade therapy in cancer treatment through modulating gut microbiota. We also discuss the possibility that chronic infections or inflammation may impact on PD-1 and PD-L1 blockade therapy.

Keywords: cancer immunotherapy; efficacy; gut microbiota; programmed death 1; programmed death ligand 1.

Figure 1

The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in tumor evasion and cancer immunotherapy. In the tumor microenvironment, T cells were activated after antigen-presenting cells recognized tumor neoantigens. The IFN-γ produced by activated T cells induced the expression of PD-1 ligands on cancer cells and immune cells. Afterward, the engagement of PD-1 by PD-L1 between T cells and antigen-presenting cells will lead to T cell dysfunction. PD-1/PD-L1 blockade using relevant antibodies can inhibit this process, therefore, offering a chance for T cells to continue being effectors. Abbreviations: TCR, T-cell receptor; MHC, major histocompatibility complex; IFN-γ, interferon gamma; IL-10, interleukin 10.

Figure 2

Discovery and validation of the therapeutic significance of commensal microbiota by facilitating anti-programmed death ligand-1 (PD-L1) efficacy. (A) Two genetically similar mice, JAX and TAC, differing in commensal microbes carried were cohoused, while another pair was housed separately. Cohousing resulted in the TAC mice obtaining the JAX microbial phenotype, with reduced tumor growth as compared to the TAC mice housed separately. JAX mice had no differences in tumor size when cohoused with TAC mice compared to separate housing. This suggests that JAX mice are colonized by commensal microbes that facilitate anti-tumor immunity. (B) TAC mice were treated with PD-L1 mAb, JAX mice fecal material, both the PD-L1 mAb and JAX mice fecal material or not treated. Administration of JAX fecal material alone resulted in slower tumor growth to the same degree as treatment with PD-L1 mAb. Combination treatment with both the PD-L1 mAb and JAX fecal material showed the slowest tumor growth, indicating that commensal microbes play a therapeutic role in anti-tumor immunity. Data were adapted from Sivan et al (38). Further findings in this study have demonstrated that Bifidobacterium is the responsible bacterial species that contributes to improving the efficacy of PD-L1 blockade therapy.