Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy

Abstract

Development of drug resistance represents the major cause of cancer therapy failure, determines disease progression and results in poor prognosis for cancer patients. Different mechanisms are responsible for drug resistance. Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance: drug transport and metabolism; alteration of drug targets; DNA damage repair; and deregulation of apoptosis, autophagy, and pro-survival signaling. On the other hand, a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance. Gut microbiota represents a new player in the regulation of a patient's response to cancer therapies, including chemotherapy and immunotherapy. In particular, commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer. Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs, such as oxaliplatin, gemcitabine, and cyclophosphamide. Recently, it has been shown that such bacteria can produce extracellular vesicles (EVs) that can mediate intercellular communication with human host cells. Indeed, bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy. On the other hand, host cells can also deliver human EVs to commensal bacteria and similarly, regulate gene expression. EV-mediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.

Keywords: Gut microbiota; cell-to-cell communication; chemotherapy; extracellular vesicles; immune checkpoint inhibitor; immunotherapy; miRNAs; resistance.

Figure 1

Gut microbiota and host cells: EV-mediated crosstalk. Bacterial EVs can deliver functional and active RNA molecules to host cells, such as gut epithelial cells, immune cells, and potentially cancer cells, and regulate their biological functions by affecting gene expression in recipient cells. Microbe-associated molecular patterns carried by bacterial EVs can activate the immune system locally (mesenteric lymph nodes) or systemically by reaching the circulatory system (spleen, peripheral lymph nodes) to modulate cancer immune responses. Host cells, such as intestinal epithelial cell can affect the gut microbiota by secreting EV-encapsulated miRNAs, which can regulate intestinal bacterial functions and composition by targeting microbial gene expression and potentially modulate the responses to cancer treatment. (Figure is created with BioRender.com). EVs: extracellular vesicles