Probiotics destroy immune suppression and stimulate tumor growth?

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Probiotics destroy immune suppression and stimulate tumor growth?

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Probiotics destroy immune suppression and stimulate tumor growth?

Are probiotics harmful to health? Destroy immune suppression, stimulate tumor growth, and become a “cancer accomplice”.

Lactobacillus is a well-known figure in the yogurt industry. In people’s traditional cognition, it is a beneficial flora that promotes the function of the gastrointestinal tract.

However, we didn’t expect that this “big-eyed and big-eyed” lactic acid bacteria also betrayed the revolution and became a The “accomplice” of pancreatic cancer.

On February 8, 2022, the team of Tracy L. McGaha of the University of Toronto, Canada published a research paper entitled Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity in Immunity , a sub-journal of Cell .

It is revealed that lactic acid bacteria activate tumor-associated macrophages (TAM) to promote the growth of pancreatic ductal carcinoma by metabolizing tryptophan in food .

Tryptophan (Trp) is one of the essential amino acids in the human body, and its metabolites have functions such as immunity, metabolism, and neuromodulation . Neurological diseases, infectious diseases, autoimmune diseases, tumors and other diseases.

Tumor-associated macrophages are macrophages infiltrated in tumor tissue. As the “wallpaper” in immune cells, some TAMs can kill tumor cells, but some TAMs can promote tumor growth, metastasis and invasion.

Research contents

AhR is key to suppressing tumor immunity and promoting pancreatic cancer growth

The researchers first detected the differential gene expression of TAM in pancreatic ductal carcinoma by RNA-seq. Compared with normal macrophages, the expression of tumor -promoting genes Arg1, Nos2 and Cd274 was significantly up-regulated in TAM . Among the 880 up-regulated genes, the researchers noted that Cyp1b1, the gene encoding the aryl hydrocarbon receptor (AhR), a receptor for serine metabolites, was also significantly up-regulated. The researchers then found decreased expression of CD45 and increased expression of MHCII, CD40 and PDL1 in AhR-deficient mice, suggesting an immunoregulatory role for AhR .

Image from Immunity

In addition, the researchers also found that the number of T cells activated in AhR-deficient mice was increased, while the tumor weight and the proportion of invasive adenocarcinoma were significantly lower than those in the control group. The survival curve also showed that AhR-deficient mice had better survival. .

The researchers then used the AhR inhibitor CH223191 to further verify its effect on immune infiltration phenotype and tumor growth. CH223191 can increase the anti-tumor effect of PDL1 antibody, and the combination of the two can effectively improve the survival of mice . These data demonstrate that AhR is able to inhibit T cell maturation, thereby subverting the immunosuppression of pancreatic cancer cells .

AhR alters cellular gene transcription

Using mass cytometry (CyTOF) and single-cell sequencing techniques, the researchers identified three groups of macrophage clusters in tumor tissue, respectively. The gene enrichment of these three groups of macrophages was analyzed by iGSEA, and the results showed that AhR can affect the interferon response pathways including IFNg, IRF8, IFI16, IFNb and MYD88, as well as interferon-induced transcription factors, signal transduction networks and inflammation. mediators of gene expression .

Based on the above data, the researchers analyzed the immune regulatory network centered on STAT1, and used CD8 and INFγ antibodies to verify the immune effect on tumors.

Lactic acid bacteria activate AhR by metabolizing tryptophan

Lactic acid bacteria can metabolize tryptophan to produce indole. In order to find the source of AhR activation, the researchers first found that the broad-spectrum antibiotic Abx can inhibit tumor growth in mice. After that, the tumors were treated with lactic acid bacteria-intolerant Amp and tolerable Vanc as controls, respectively. The results showed that the use of Amp to inhibit lactic acid bacteria can effectively increase the expression of PDL1 and MHCII in cells to improve the immune response effect, thereby effectively inhibiting tumor growth .

Among several common lactic acid bacteria, L. reuteri and L. murinus can produce IAA and ILA, two products that activate AhR, while L. murinus produces more, so the researchers transplanted L. murinus into the gut of germ-free mice. Studying its effect on the growth of pancreatic cancer, the results showed that L. murinus can not only promote tumor growth and inhibit tumor immunity, but also promote the expression of Arg1, Ido1, Il10, which promote oncogenes .

Effects of dietary regulation

Since tryptophan is obtained through food, dietary changes must have an impact on pancreatic cancer growth. The research team tested the effect of tryptophan metabolism on pancreatic cancer by adding IAA and ILA to a diet deficient in tryptophan. The results showed that the tumor weight of mice on a tryptophan-deficient diet was half that of the control group, and the addition of IAA and ILA could significantly increase the tumor weight . Changes in diet occur accordingly.

Influence on the prognosis of pancreatic cancer patients

Subsequently, the researchers analyzed single-cell sequencing results and TCGA data of tumor patients and found that patients with high AhR expression had worse survival, while AhR was negatively correlated with CD8+ T cell-related gene expression. The human pancreatic cancer cell experiments also verified the promoting effect of AhR on the growth of pancreatic cancer cells.

Summary

Most studies have focused on the positive regulation of microbes on tumors, but this study focused on the negative immune regulation of gut microbes on tumors, breaking people’s inherent impression of gut probiotics.

It is demonstrated that lactic acid bacteria activate tumor-associated macrophage AhR by metabolizing tryptophan, which ultimately promotes pancreatic cancer growth and destroys the inhibitory effect of immune checkpoints .

Pancreatic cancer is known as the “King of Cancer”. The poor treatment effect and low survival rate of pancreatic cancer patients have always been a problem for scientific researchers and medical personnel.

The team is working with clinicians to carry out corresponding clinical trials. It is believed that in the near future. In the future, the survival of pancreatic cancer patients can be improved by dietary modification or effective inhibitors.

References

1. Kebria Hezaveh et al, Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity, Immunity, DOI https://doi.org/10.1016/j.immuni.2022.01.006

2. Michael Platten et al, Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond, Nature reviews, DOI 10.1038/s41573-019-0016-5

Probiotics destroy immune suppression and stimulate tumor growth?

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