Colorectal cancer: the intestinal microbiota stimulates antitumor immunity
For the first time, a Swiss team has attempted to understand the immune mechanisms and the role of the bacterial microenvironment of the tumor in the survival of patients suffering from colorectal cancer.
The presence of lymphocytes infiltrating tumors is recognized as a prognostic factor in oncology, but the origin of lymphocyte recruitment remains obscure. The researchers therefore explored the chemokines involved in T-cell recruitment in colorectal cancer (CRC) and the role of the bacterial microenvironment, whose chemotactic aspect had never previously been evaluated. For this purpose, CRC tissue and healthy tissue were compared. The expression of genes encoding chemokines and bacterial 16S rRNA were quantified; chemokine receptor expression was evaluated both in vivo and in vitro.
Intestinal microbiota used to predict survival
Surprisingly, stimulation of cancer cells by digestive tract bacteria in vivo and in vitro induced upregulation–and even de novo expression–of several genes, increasing the recruitment of T-cells within the tumor. The authors even showed that infiltration by T-cells was significantly associated with the presence of certain bacterial families, with a correlation between certain bacteria and the level of expression of chemokine genes. In the experiments conducted in vitro, species such as Escherichia coli or Bacteroides fragilis promoted expression of these genes. In vivo analyses in humans showed that Firmicutes, especially Lachnospiraceae and Ruminococcaceae, had a far greater association with lymphocyte recruitment. An abundance of Bacteroides and Proteobacteria was also correlated with overexpression of chemokines. In mice, this overexpression was reduced drastically by antibiotic treatment, with the Bacteroidetes and Firmicutes families being particularly affected. Rather surprisingly, bacteria such as Fusobacteria, associated with a more serious prognosis and found in tissue with little infiltration, were capable of stimulating T-cell recruitment. The authors consider that certain bacteria could be able to stimulate T-cell attraction while others inhibit it (Fusobacterium nucleatum is already known to be capable of inhibiting T-cell and NK-cell functions), but further studies will be needed to confirm this.
By which mechanism?
The bacteria of the intestinal microbiota therefore indeed play an inductive role. The researchers explain this phenomenon by the role of other receptors. The expression of chemokine genes by bacteria is thought to be triggered by stimulation of TLRs (Toll-Like Receptors), receptors found on the surface of cancer cells that are able to recognize the bacterial components. This hypothesis was proven by the use of purified TLR agonists, causing an increase in chemokines. This study shows that CRC cancer cells are the main source of chemokines and reveals the essential role of the microbiota in immune induction. The overexpression of chemokines in cancer tissue (mainly CCL5, CXCL9 and CXCL10) was associated with an improvement in the survival of patients in previous studies. The authors demonstrate that chemokine receptors (CCR5 and CXCR3) are widely expressed by the different tissue infiltrated by lymphocytes, predicting a favorable clinical course. In the same way, the results show that the tumor cells overexpress chemokine genes. This overexpression was not observed in vitro, suggesting that a microenvironment agent has a key action in the in vivo environment. The discovery of these mechanisms could allow for the development of innovative treatments based on modulation of the microbiota with the aim of triggering lymphocyte infiltration of tumor tissue, thus increasing patient survival.
E. Cremonesi et al. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut, p. gutjnl-2016-313498, févr. 2018.