Microbiota and Extracellular Vesicles in Anti-PD-1/PD-L1 Therapy

Abstract

Cancer is a deadly disease worldwide. In light of the requisite of convincing therapeutic methods for cancer, immune checkpoint inhibition methods such as anti-PD-1/PD-L1 therapy appear promising. Human microbiota have been exhibited to regulate susceptibility to cancer as well as the response to anti-PD-1/PD-L1 therapy. However, the probable contribution of bacterial extracellular vesicles (bEVs) in cancer pathophysiology and treatment has not been investigated much. bEVs illustrate the ability to cross physiological barriers, assemble around the tumor cells, and likely modify the tumor microenvironment (EVs). This systematic review emphasizes the correlation between cancer-associated extracellular vesicles, particularly bEVs and the efficacy of anti-PD-1/PD-L1 therapy. The clinical and pharmacological prospective of bEVs in revamping the contemporary treatments for cancer has been further discussed.

Keywords: anti-PD therapy; cancer; extracellular vesicles; microbiota.

Figure 1

Summary of methodology.

Figure 2

Host–microbiota interaction and anti-tumor response.

Figure 3

Effect of fecal microbiota transplantation (FMT) from responders and non-responders of anti-PD-1 therapy in tumor-engrafted germ-free mice.

Figure 4

Exosomal PD-L1 correlates with tumor response and resistance to anti-PD1 therapy: (A) Tumor cell-derived extracellular vesicles cause immune suppression by the direct engagement of PD-1 on T cells (B) PD-L1/PD-1 interaction is blocked by the presence of anti-PD-1 monoclonal antibody (C) Tumor suppression: PD-L1 expression levels in exosomes are inversely related to the tumor’s response to immunotherapy. PD-L1 mRNA levels significantly declined from the start of treatment in patients with complete and partial responses to anti-PD-1therapy, characterized by low exosome release, T cell reactivation, and tumor shrinkage. (D) Tumor relapse: PD-L1 expression levels in exosomes are directly related with tumor resistance to immunotherapy. PD-L1 mRNA significantly increased in patients with a tumor relapse, characterized by increased exosome release, T-cell inhibition, and tumor growth. Downwards arrow—decreased, Upwards arrow—increased.

Figure 5

In healthy conditions, luminal epithelium is intact and fewer bEVs can pass transcellularly into the systemic circulation. In microbial dysbiosis, intestinal barrier dysfunction facilitates rapid transport of bEVs into the systemic circulation, induction of immune activation, and intervention in carcinogenesis/tumor progression.

Figure 6

Potential applications of bacterial extracellular vesicles.