The introduction of bacteria into the microenvironment of a tumor creates a state of acute inflammation that prompts the immune system’s primary responder cells to attack a tumor rather than protect it, according to researchers from UNSW Sydney and the Garvan Institute of Medical Research.
With the earliest signs of bacterial infection, the first cells at the scene are white blood cells called neutrophils, which play an important role in fighting infection.
While they generally protect against disease, they are notorious for promoting tumor growth. High levels of them in the blood are typically associated with poorer outcomes in cancer, in part because they produce molecules that shield the tumor by suppressing the other elements of the immune system.
The team of scientists discovered that injecting inactivated samples of the microbe Staphylococcus aureus into the tumor microenvironment – the area surrounding the tumor – reversed the protective function of neutrophils.
The research, published in the journal cancer research, was led by Associate Professor Tatyana Chtanova at UNSW’s School of Biotechnology and Biomolecular Sciences and Head of the Laboratory of Innate and Tumor Immunology at Garvan. A/Prof Chtanova says these results have helped advance our understanding of acute inflammation to advance microbial therapy of cancer.
“In our study, we tried to develop new immunotherapies that use different mechanisms of action that could complement and improve existing immunotherapies,” says A/Prof. Chtanova.
“We show how acute inflammation can be used to achieve sustained anti-tumor function in immune cells. We also show how microbial therapy can be successfully combined with an existing type of therapy, called checkpoint inhibitor therapy, to boost anti-cancer abilities.”
Researching new ways to stimulate the immune system to fight cancer
Working on a number of animal cancer models, including Lewis lung carcinoma, triple-negative breast cancer, melanoma and pancreatic cancer, the presence of bacteria stimulated neutrophils to destroy tumors.
“Using the immune system to fight cancer has been one of the biggest breakthroughs in cancer therapy in the past two decades, but currently, immunotherapy is used to improve T-cell function [another important type of white blood cell] does not work in all cancers,” says A/Prof. Chtanova.
“We decided to use a different type of immunotherapy that targets neutrophils to understand how the generation of acute inflammation in the tumor’s immunosuppressive microenvironment affects outcomes.”
The team examined the tumors in real time using a unique imaging technique known as intravital imaging.
“Since attacking bacteria is the reason neutrophils exist, we had a good hunch that introducing bacteria would bring neutrophils to the site and activate them. We’ve found that getting them to kill the tumors and chew up their matrix is very effective,” she says.
The study also found that upon contact with bacteria, neutrophils begin secreting molecules that attract fighter T cells as reinforcement.
“We have shown that microbial therapy is an effective booster to checkpoint inhibitor therapy. We hope that this synergistic effect will ultimately lead to better treatments to improve outcomes for patients with advanced or previously untreatable cancer,” says lead author of the study, Dr. Andrew Yam, clinical medical oncologist at Kinghorn Cancer Center and graduate student at Garvan.
This study focused on primary tumors, the first tumor in the body. “So far we have shown that our microbial therapy can inhibit the growth of primary tumors and also protect against tumor recurrence, which represents a major clinical challenge,” says A/Prof. Chtanova. “This suggests that our microbial therapy achieves not just short-term and localized, but long-lasting and systemic anti-tumor immunity.
“Our next step is to extend these findings to develop a way to treat cancer that has metastasized to multiple sites.”