"Immunity" Lactobacillus disrupts immunosuppression and stimulates tumor growth

Lactic acid bacteria, in people's traditional cognition, it is a kind of beneficial flora that promotes the function of the gastrointestinal tract

However, we did not expect that this lactic acid bacteria also betrayed the revolution and became an "accomplice" of pancreatic cancer

On February 8, 2022, the team of Tracy L.

The study found that lactic acid bacteria promote the growth of pancreatic duct cancer by activating tumor associated macrophages (TAMs) 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

Tumor-associated macrophages are macrophages infiltrating tumor tissue

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

For the first time, the researchers detected differential gene expression of TAMs in pancreatic duct cancer by RNA-seq

In addition, the researchers found an increase in the number of activated T cells in AhR-deficient mice, while tumor weight and the proportion of invasive adenocarcinomas were significantly lower than in controls

The researchers then used the AhR inhibitor CH223191 to further validate its effect on immune infiltration phenotype and tumor growth

AhR alters cellular gene transcription

Using mass cytometry (CyTOF) and single-cell sequencing, the researchers identified three groups of macrophage clusters in tumor tissue, respectively

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

Lactic acid bacteria activate AhR by metabolizing tryptophan

Lactic acid bacteria can metabolize tryptophan to produce indole

Among several common lactic acid bacteria, Lactobacillus reuteri and Lactobacillus murine can produce two products that activate AhR, IAA and ILA, while Lactobacillus murine produces more products, so the researchers transplanted Lactobacillus murine into sterile in the intestines of mice

Effects of dietary modification

Since tryptophan is obtained through food, changes in diet must have an effect on pancreatic cancer growth

Impact 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 poorer survival, while AhR was negatively correlated with CD8+ T cell-related gene expression
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The human pancreatic cancer cell experiments also verified the promoting effect of AhR on the growth of pancreatic cancer cells
.

Summarize

Most of the previous studies focused on the positive regulation of microbes on tumors, while this study focused on the negative immune regulation of intestinal microbes on tumors, breaking people's inherent impression of intestinal probiotics
.

The results showed that Lactobacillus activates AhR in tumor-associated macrophages by metabolizing tryptophan, which ultimately promotes pancreatic cancer growth and subverts the inhibitory effect of immune checkpoints
.

Pancreatic cancer is known as "the king of cancer"
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The poor treatment effect and low survival rate of pancreatic cancer patients have always been a difficult problem for researchers and medical staff
.

The team is working with clinicians on corresponding clinical trials
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Believe in the near future
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In the future, the survival rate of pancreatic cancer patients could be improved with dietary modifications 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