Microflora helps oncologists
Can the success of cancer immunotherapy depend on intestinal bacteria?
Can the response to cancer immunotherapy depend on the bacteria that form in the intestine and move into the tumor? – this is reported by the press release UT Southwestern with reference to the Journal of Experimental Medicine (Fu et al., Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling – VM).
A study conducted by scientists from the University of Texas Southwestern Medical Center and the University of Chicago shows that gut bacteria can penetrate tumor cells and increase the effectiveness of experimental immunotherapy targeting the CD47 protein.
Using mouse models of malignant neoplasms, the scientists found that the intestinal microbe Bifidobacterium accumulates in tumors, turning tumors that do not respond to anti-CD47 therapy into sensitive ones.
The team's study found that the response to treatment depends on the type of bacteria living in the intestines of animals. Then they determined the mechanism: the combination of antibodies against CD47 and intestinal bacteria works through the stimulator of interferon genes (STING) – the first line of defense of the body against infection.
Different mice were used in the experiments: taking antibiotics and grown in an environment that does not contain microbes.
In one experiment, they studied mice raised in two different rooms with different mixtures of bacteria in their intestines. One group reacted to anti-CD47, while the other did not. The second group began to react, however, after being placed with the respondents, indicating that oral transfer or contact transfer of intestinal bacteria occurred between the groups, the researchers say.
The CD47 protein is expressed in large numbers on the surface of many cancer cells, where it acts as a "don't eat me" signal to the macrophages of the immune system, commonly called leukocytes. As a result, anti-CD47, also known as CD47 blockade therapy, is currently being investigated in several clinical trials. However, studies on mice prior to these trials yielded mixed results, and only some mice responded to anti-CD47 therapy," explains corresponding author Yang–Xin Fu, MD, professor of pathology, immunology and radiation at the University of Texas.
"We felt we had to improve anti-CD47 therapy and understand the mechanisms," he says. This made them think about the gut microbiome –the bacteria that grow in the gut and promote digestion. It is known that this bacterial ecosystem, sometimes called the microbiota, also affects the ability of the intestine to resist pathogens and the host's response to cancer immunotherapy.
"But how the microbiota does this is unclear,– Fu says. – The study showed that some bacteria from the intestine move into the tumor and enter the cells or microenvironment, where the bacteria contribute to the ability of CD47 blockade to attack the tumor. We found that this happens through an immune signaling pathway called the interferon gene stimulator (STING)."
The findings suggest that the probiotic may someday be used to improve anti-CD47 therapy, says Fu, a researcher at the Institute for Cancer Prevention and Research (CPRIT) and the holder of the Mary Nell and Ralph B. Rogers Professor of Immunology at Southwestern Utah.
The researchers also found that mice with tumors that normally respond to anti-CD47 treatment do not respond if their gut bacteria have been destroyed by antibiotics. On the contrary, anti-CD47 treatment became effective in mice that usually do not respond to therapy when these animals were injected with bifidobacteria, a type of bacteria that is often found in the gastrointestinal tract of healthy mice and humans.
The scientists also found that bacteria migrate into tumors by activating the STING immune signaling pathway. This triggers the production of immune signaling molecules, such as type 1 interferons, and the activation of immune cells that appear to attack and destroy the tumor as soon as the anti-CD47 agent cancels the CD47 "don't eat me" label, the researchers report. The researchers found that mice that are genetically unable to activate interferon type 1 do not respond to the method of bacterial immunotherapy. Similarly, mice unable to access the STING pathway have not demonstrated any benefit from the combined bacterial immunotherapy approach, which confirms the importance of STING signaling.
"It is possible that more than one type of gut microbiota can boost tumor immunity in a similar way, and we would like to investigate this," adds Fu.
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