Australian cancer researchers have shown that neutrophils can be converted from tumour growth promoters to tumour killing phenotypes through the direct application of microbial therapy.
Using animal tumour models, scientists at the Garvan Institute of Medical Research, Sydney, showed that injecting bacterial particles into a tumour’s microenvironment created a state of acute inflammation that led to a rapid and dramatic increase in activated cytotoxic neutrophils.
The experiments, led by Dr Andrew Yam, a medical oncologist at the Kinghorn Cancer Centre and PhD student at Garvan, showed that the activated tumour neutrophils switched from being producers of vascular endothelial growth factor (VEGF) to highly motile neutrophils that had enhanced anti-tumour effects.
“The neutrophil clusters remodelled tumour tissue and repressed tumour growth,” the research team reported in Cancer Research.
Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8+ T cell recruitment.
“Microbial therapy also boosted CD8+ T cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumour-bearing mice and provided protection in a model of tumour recurrence,” they noted.
The observations were made after injection of inactivated Staph. aureus bacteria into tumour models, “stimulating the neutrophils to destroy the tumour in a range of animal cancer models, including Lewis lung carcinoma, triple-negative breast cancer, melanoma and pancreatic cancer.”
“These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumour neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers,” the researchers concluded.
“We’ve shown that microbial therapy is an effective booster for checkpoint inhibitor therapy … we hope this synergistic effect will ultimately lead to better treatments to improve outcomes for patients with advanced or previously untreatable cancers,” commented Dr Yam.
“Using the immune system to fight cancer has been one of the biggest breakthroughs in cancer therapy in the last two decades, but currently immunotherapy for improving T cell function doesn’t work for all types of cancer,” said co-author Dr Tatyana Chtanova, Head of the Innate and Tumour Immunology Lab at Garvan.
“We decided to use a different type of immunotherapy that targets neutrophils, to understand how generating acute inflammation in the immunosuppressive tumour microenvironment affects outcomes,” she said.
“Since attacking bacteria is the reason for neutrophils’ existence, we had a good inkling that introducing bacteria would bring neutrophils to the site and activate them. We discovered that it’s very effective in getting them to kill the tumours, chewing up their matrix,” she added.