The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review

Abstract

The human microbiota comprises a group of microorganisms co-existing in the human body. Unbalanced microbiota homeostasis may impact metabolic and immune system regulation, shrinking the edge between health and disease. Recently, the microbiota has been considered a prominent extrinsic/intrinsic element of cancer development and a promising milestone in the modulation of conventional cancer treatments. Particularly, the oral cavity represents a yin-and-yang target site for microorganisms that can promote human health or contribute to oral cancer development, such as Fusobacterium nucleatum. Moreover, Helicobacter pylori has also been implicated in esophageal and stomach cancers, and decreased butyrate-producing bacteria, such as Lachnospiraceae spp. and Ruminococcaceae, have demonstrated a protective role in the development of colorectal cancer. Interestingly, prebiotics, e.g., polyphenols, probiotics (Faecalibacterium, Bifidobacterium, Lactobacillus, and Burkholderia), postbiotics (inosine, butyrate, and propionate), and innovative nanomedicines can modulate antitumor immunity, circumventing resistance to conventional treatments and could complement existing therapies. Therefore, this manuscript delivers a holistic perspective on the interaction between human microbiota and cancer development and treatment, particularly in aerodigestive and digestive cancers, focusing on applying prebiotics, probiotics, and nanomedicines to overcome some challenges in treating cancer.

Keywords: cancer; cancer therapy; chemotherapy; immune system; immunotherapy; microbiome; microbiota; nanotechnology.

Figure 1

Schematic representation of the debate performed between microbiota and immune system to maintain the tight balance between health and disease. Dysbiosis contributes to an imbalance of the immune system, leading to chronic inflammation, and may promote the development of cancer, infection, or autoimmune diseases.

Figure 2

The contribution of microbiota on the solid tumor carcinogenesis process. Human body barriers are subject to constant environmental insult and injury. Trauma and dietary factors can contribute to the breach of the mucosal barriers, leading to infection. Generally, mucosal barrier damage is rapidly repaired, and tissue homeostasis is restored. However, decreased host resiliency contributes to persistent barrier damage, leading to its disruption and failure in homeostatic repair. In these settings, the microbiota may influence carcinogenesis by (i) altering host cell proliferation and death, (ii) perturbing immune system function, and (iii) influencing metabolism [11].

Figure 3

Summary of the microbial species present in the normal oral microbiota [64].

Figure 4

Overview of the common anticancer treatments and their influence on the microbiome and vice-versa [110]. PK, pharmacokinetics; ROS, reactive oxygen species; TNF-α, tumor necrosis factor—alpha.

Figure 5

Radiotherapy may compromise the gut microbiota homeostasis by the imbalance of some genera, as depicted [146,148,149,150,151,152].

Figure 6

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 to 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. Reprinted from [176] under a CC By license.

Figure 7

The modulation of microbiota by innovative drug delivery systems to improve cancer treatment outcomes. (A) Prebiotics can be applied in nanoparticles for drug delivery, conjugated with functional groups to form to nanoparticles alone or in combination with other cancer therapeutic agents. (B) Probiotics can be enclosed into nanoparticles to protect their bioactivities. (C) Eliminate pro-tumoral bacteria by targeted antibiotic delivery avoiding dysbiosis. (D) Nanoparticles can be designed to capture bacterial products or exhibit bacterial products inhibitors. Reprinted from [202] under a CC BY license.