Cancer immunotherapy has transformed the treatment of many sorts of cancer. Yet, for reasons that remain poorly understood, not all patients get the identical profit from these powerful therapies.

One potent consider treatment final result appears to be a person’s gut microbiota -; the trillions of microorganisms that live within the human intestine -; in accordance with latest research led by investigators at Harvard Medical School and Dana-Farber Cancer Institute.

The study, done in mice and published May 3 in Nature, pinpoints how gut microbes enhance the body’s response to a standard style of immunotherapy referred to as PD-1 checkpoint blockade, currently used for the treatment of 25 types of cancer.

The research found that specific gut bacteria can affect the activity of two immune molecules -; PD-L2 and RGMb -; in addition to the interplay between them.

The work also showed that blocking the activity of either molecule or the interplay between them enhanced responses to cancer immunotherapy and optimized the body’s ability to detect and destroy cancer cells.

The engagement between PD-L2 and RGMb acts as a brake on cancer-fighting T cells, and our work shows that treatment with antibodies that block the interaction of PD-L2 with RGMb releases this brake and allows T cells to eradicate tumors.”

Arlene Sharpe, the Kolokotrones University Professor at Harvard and chair of the Department of Immunology within the Blavatnik Institute at HMS, co-senior creator

Sharpe co-led the research with Dennis Kasper, the William Ellery Channing Professor of Medicine and professor of immunology at HMS, and Gordon Freeman, professor of medication at HMS and Dana-Farber.

The study also identifies the molecule RGMb as a previously unknown accomplice in sabotaging the body’s ability to identify and destroy tumors. RGMb, primarily known for its role in nervous system development, can be found on the surface of cancer-fighting T cells. Until now, nonetheless, nobody knew it played a job in regulating T-cell responses to cancer immunotherapy.

If replicated in humans, the findings can inform the design of therapies that improve immunotherapy treatment outcomes, the researchers noted.

“Our findings offer a critical clue into a fancy puzzle and in doing so suggest concrete ways to boost the potency of cancer immunotherapy and improve patient outcomes,” said study co-first creator Joon Seok Park, a postdoctoral research fellow in immunology within the Sharpe lab. “We propose a latest approach to beat the resistance to the present cancer immunotherapies by learning from gut bacteria that help our immune system to fight cancer.”

How cancer evades immune detection and destruction

Critical to cancer’s survival and spread is its ability to evade the body’s immune defenses. Starting within the Nineteen Nineties, Sharpe and Freeman performed among the critical early work that elucidated how cancer manages to achieve this.

Sharpe’s and Freeman’s work focused on two molecules, PD-L1 and PD-L2, that reside on the surface of immune cells. Their research showed that when PD-L1 or PD-L2 interact with one other molecule, PD-1, on the surface of T cells, the activity of T cells is kept in check. Under normal conditions, this interaction functions as a brake on T cells to make sure they don’t mistakenly attack the body’s own cells and tissues.

Sharpe, Freeman, and others discovered that cancer exploits precisely this safety mechanism to evade detection and destruction by T cells. Cancer cells achieve this by expressing PD-L1 and PD-L2 on their surfaces, engaging with PD-1 and reining in T cells. Cancer immunotherapies that block the interaction of PD-1 with PD-L1 or PD-L2 release the T cells’ attack against cancer and are referred to as immune checkpoint blockade.

Such treatments, currently used for 25 types of cancer, have revolutionized cancer care, but a subset of patients don’t profit from them. Because the advent of those treatments, researchers have been trying to grasp why.

The interplay between the immune system and the gut microbiota has been the main target of Kasper’s work for a few years. His lab has identified not only mechanisms of regulation but in addition specific microbial molecules and microbial enzymes answerable for modulating the immune system.

The notion that gut microbes could affect cancer immunotherapy shouldn’t be entirely latest. Recent studies have found tantalizing clues in regards to the role that gut microbes play in immunotherapy treatment outcomes. Until now, nonetheless, a critical query remained unanswered: How?

A latest player enters the scene

In the brand new study, the researchers used mice whose colons were seeded with gut microbiota from patients with cancer. A few of those patients had responded well to immunotherapy, while others had not experienced much profit. These animals’ response to immunotherapy mimicked the treatment response within the humans whose gut microbes now lived of their intestines.

Comparing the immune system profiles of the 2 groups of mice, the researchers identified telltale differences in various immune cells involved in cancer detection and destruction. The finding suggested that gut microbiota altered the immune cells’ behavior and, due to this fact, response to immunotherapy.

Mice seeded with gut microbes from patients that had themselves responded well to cancer immunotherapy had lower levels of PD-L2 on a category of immune cells referred to as antigen-presenting cells. These cells play a critical role in rallying the body’s immune defenses. They achieve this by patrolling the body for pathogens or tumors and presenting these foreign or abnormal proteins to T cells for destruction. Conversely, mice seeded with gut microbes from patients with a poor response to immunotherapy had increased levels of the PD-L2 molecule.

To tease out the effect of specific gut microbes, the researchers treated groups of mice with broad-spectrum antibiotics, which kill gut bacteria. Antibiotic-treated mice didn’t reply to immunotherapy that blocked the PD-1 molecule. These mice, nonetheless, had high levels of PD-L2, the opposite molecular brake that typically acts through PD-1. Animals that had a sturdy response to the identical treatment had lower levels of PD-L2.

Intrigued that PD-1 blockade didn’t work, the researchers hypothesized that PD-L2 acts as a brake on T cells, not through PD-1 alone but through one other molecular accomplice. The researchers turned their attention to RGMb, which the Freeman lab had previously shown that RGMb and PD-L2 regulated immune tolerance in lungs.

When the scientists treated the mice that had not responded to anti-PD-1 therapy alone with antibodies that blocked RGMb, these animals experienced each a rise in cancer-fighting T cells and rapid overall improvement.

“The interplay between the microbiota and immune cells within the anticancer response just got clearer, and with the identification of RGMb as PD-L2’s molecular accomplice, we’ve one other goal for cancer immunotherapy,” Freeman said.

Further analyses showed that the interaction between RGMb and PD-L2 relied on the composition of gut microbes. The researchers found that certain gut microbes could affect the degrees of each molecules.

Mice with cancer whose intestines had been seeded with certain gut microbes had levels of RGMb on their T cells six times lower than animals with microbe-free guts and responded to anti-PD-L1 or anti-PD-1 therapy. Compared, mice with depleted gut microbiota didn’t reply to these treatments and had higher levels of RGMb on their T cells, especially on T cells that had infiltrated their tumors.

Likewise, mice whose guts were seeded with microbiota from patients with poor treatment responses also had higher levels of RGMb, a finding suggesting that patients who don’t mount a superb response to cancer immunotherapy harbor higher levels of RGMb on their T cells, which in turn interferes with their immune cells’ antitumor response.

Disabling the activity of either PD-L2 or RGMb was sufficient to preserve T cells’ antitumor activity and ensured a sturdy response to PD-L1 and PD-1 therapy. Remarkably, blocking the activity of PD-L2 led to a potent antitumor response in animals treated with one other type of cancer immunotherapy referred to as dendritic cell therapy. The commentary suggests that modulating PD-L2 activity holds promise for enhancing the response to multiple sorts of cancer immunotherapy.

Gut microbes as regulators of immune response

Altering the composition of the gut microbiota in several groups of mice revealed that one organism, C. cateniformis, suppressed PD-L2 levels and rendered immunotherapy more practical in mice with cancer.

Provided that the human gut is home to hundreds of bacterial species, this microbe might be not the one organism able to regulating antitumor immunity, the researchers said.

The finding suggests that specific microbial molecules might be harnessed in the shape of small-molecule drugs to reinforce the immune system’s ability to regulate cancer. Such treatments could complement or be a substitute for traditional antibody-based cancer immunotherapy.

A small-molecule approach would have the added appeal of being cheaper to develop and store and easier to deliver into the body, Sharpe noted. Small-molecule medicines are generally given as pills, while cancer immunotherapy is run in the shape of intravenously infused antibodies.

The researchers caution that while their work reveals a critical piece of the puzzle, it is probably going only certainly one of several ways through which the immune system and the microbiome interact in cancer.

“This is probably going only the start of the story,” said Francesca Gazzaniga, co-first creator on the study and a former postdoctoral researcher within the Kasper lab, now an assistant professor of pathology at HMS and principal investigator at Massachusetts General Hospital. “Cancer, the immune system, and the microbiome are astoundingly complex individually, but once you put these systems together, the resulting interplay is exponentially more intricate.”

“There are likely many other ways through which the microbiome can affect cancer immunity normally and cancer immunotherapy specifically,” Kasper said. “With this work, we have found an entire latest way of how the gut microbiota affects not only the efficacy of cancer treatments but cancer immunity normally.”

Source:

Journal reference:

Park, J. S., et al. (2023). Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance. Nature. doi.org/10.1038/s41586-023-06026-3.