Fungi, host immune response, and tumorigenesis

Abstract

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy. We reported that the Malassezia species associated with scalp and skin infections, colonize in human PDAC tumors and accelerate tumorigenesis via activating the C3 complement-mannose-binding lectin (MBL) pathway. PDAC tumors thrive in an immunosuppressive microenvironment with desmoplastic stroma and a dysbiotic microbiome. Host-microbiome interactions in the tumor milieu pose a significant threat in driving the indolent immune behavior of the tumor. Microbial intervention in multimodal cancer therapy is a promising novel approach to modify an immunotolerant ("cold") tumor microenvironment to an immunocompetent ("hot") milieu that is effective in eliminating tumorigenesis.

Keywords: complement system; gut microbiome; immunotherapy; mycobiome; pancreatic cancer.

Graphical abstract

Figure 1.

Mouth-gut microbiome as commensals and/or pathobionts. The flowchart represents diverse, anatomical site-specific predominance of a healthy microbiota profile in the oral-gut axis. Acute inflammatory response directs the development of a normal immune system, whereas chronic low-grade inflammation causes leaky-gut resulting specific microbial colonization in various tissues, leading to disease conditions. HCC, hepatocellular carcinoma; PDAC, pancreatic ductal adenocarcinoma.

Figure 2.

Fungal pathogens induce inflammatory microenvironments. C-type lectin receptors recognize fungal invasion through surface receptors on molecules of the innate immune system or via soluble mannose-binding lectin (MBL)-mediated sensing. The proinflammatory storm further “trains” an adaptive immune system. Malassezia spp. secrete hydrolase to release host lipids and indoles, which act as potent agonists for AhRs that can trigger immune cell activation. Malassezia spp. can also activate the C3 complement-MBL pathway to promote an immunosuppressive tumor milieu, as in PC. AhR, aryl hydrocarbon receptor; CD4+, cluster of differentiation 4 positive; CLR, C-type lectin receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; PC, pancreatic cancer; ROS, reactive oxygen species; Treg, regulatory T-cells.

Figure 3.

Treating fungal-induced inflammatory microenvironments. Immune-indolent tumors can be targeted in anti-CTL-4 and anti-PD-1 therapy that downregulates immunosuppressive Tregs and upregulates T-cell activity. In contrast, CD23 inhibitors target a wide range of immune responses, including activation of macrophages, subsequent secretion of proinflammatory mediators, which include TNF-α, IL-6, and NO, as well as B- and T-cell diffentiation. CD23, a low-affinity receptor for IgE; CTL, cytotoxic T lymphocytes; IL, interleukin; NO, nitric oxide; PD-1, programmed cell death protein 1.