Intratumour microbiome of pancreatic cancer

Abstract

Pancreatic cancer is a high mortality malignancy with almost equal mortality and morbidity rates. Both normal and tumour tissues of the pancreas were previously considered sterile. In recent years, with the development of technologies for high-throughput sequencing, a variety of studies have revealed that pancreatic cancer tissues contain small amounts of bacteria and fungi. The intratumour microbiome is being revealed as an influential contributor to carcinogenesis. The intratumour microbiome has been identified as a crucial factor for pancreatic cancer progression, diagnosis, and treatment, chemotherapy resistance, and immune response. A better understanding of the biology of the intratumour microbiome of pancreatic cancer contributes to the establishment of better early cancer screening and treatment strategies. This review focuses on the possible origins of the intratumour microbiome in pancreatic cancer, the intratumour localization, the interaction with the tumour microenvironment, and strategies for improving the outcome of pancreatic cancer treatment. Thus, this review offers new perspectives for improving the prognosis of pancreatic cancer.

Keywords: Chemoresistance; Diagnosis; Intratumour microbiome; Pancreatic cancer; Prognosis; Tumour microenvironment.

Figure 1

The origin and localization of the intratumour microbiome in pancreatic cancer. The microbiome in pancreatic ductal adenocarcinoma (PDAC) may originate from the gut and the oral cavity. The microbiome located in the oral cavity and gut can reach the pancreas via the pancreatic duct. But also exists the possibility of drainage via blood and lymph. The microbiome located in the gut migrates through the damaged intestinal epithelial barrier into the pancreas via venous blood, especially in the inferior gastrointestinal tract. In the case of oral microbiome, it can also enter the pancreas via the venous or lymphatic drainage. And the PDAC intratumour microbiome locates in tumour cells, immune cells and outside cells.

Figure 2

The intratumour microbiome-immune-pancreatic cancer axis. The intratumour fungi can activate the complement 3 (C3) complement cascade through the "lectin activation pathway". And C3a, as a fragment after C3 complement cascade reaction, promotes pancreatic ductal adenocarcinoma (PDAC) cells proliferation by binding to C3a receptors on the surface of cancer cells. Moreover, the intratumour fungi (Malassezia globosa or Alternaria alternata) and their cell-free extracts facilitate interleukin (IL)-33 secretion through activation of the dectin-1 receptor-mediated Src-Syk-CARD9 pathway. And IL-33 secretion promotes T helper 2 cell, group 2 innate lymphoid cells and Tregs enrichment in tumour microenvironment (TME), thus promoting PDAC progression. The intratumour bacteria promotes the secretion of neutrophil chemokines in the TME of PDAC thereby promoting tumour-associated neutrophils 2 (TAN2) enrichment in the TME. A portion of the effect of TAN2 may be through neutrophil extracellular traps. The PDAC intratumour bacteria also reduces the TAM1 polarization and decreased the antigen-presenting ability of TAM1 though through activation of toll-like receptors (TLR)2 and TLR4 on the surface of cells. TAM1 inhibition is accompanied by an increase in TAM to TAM2 conversion. It also promotes the secretion of IL-1β through TLR4 on the surface of PDAC cells. And IL-1β secretion promotes TAM2 activation through an indirect pathway that activates pancreatic stellate cells. Finally, the high diversity of intratumour microbiome promotes the activation of CD8⁺ T cells, which inhibits PDAC. C3: Complement 3; PDAC: Pancreatic ductal adenocarcinoma; Th2: T helper 2 cell; ILC2: Group 2 innate lymphoid cells; TME: Tumour microenvironment; TAN2: Tumour-associated neutrophils 2; NETs: Neutrophil extracellular traps; TAM: Tumour-associated macrophages; TLR: Toll-like receptors; PSCs: Pancreatic stellate cells.