A groundbreaking study conducted by researchers from McGill University, the Lady Davis Institute for Medical Research (LDI) at the Jewish General Hospital, the Princess Margaret Cancer Centre, and MIT has identified a new approach to combat aggressive breast cancers by training neutrophils, the body's first responders, to directly kill tumor cells. This research offers new hope for breast cancer patients who do not respond well to existing immunotherapies.
Traditional immunotherapies primarily focus on reactivating tumor-specific T cells, which have limited effectiveness in breast cancers classified as immunologically cold tumors, meaning tumors that lack significant T cell infiltration.
The new study, published in Science Advances, presents an alternative approach that harnesses the innate immune system by educating neutrophils to acquire tumor-killing properties. The researchers discovered that combining systemic Toll-like receptor (TLR) agonists with mitochondrial complex I inhibitors stimulates neutrophils to produce reactive oxygen species (ROS) and cytotoxic granules, thereby directly attacking breast cancer cells, independent of cytotoxic T cell activity.
According to John Heath, former postdoctoral fellow at the LDI and currently at the Princess Margaret Cancer Centre in Toronto, and first author of the study, "our research has shown that by harnessing the power of innate immunity, we can develop a new class of therapies that can effectively target and kill breast cancer cells, even in the absence of T lymphocyte inflammation."
"Our findings demonstrate that neutrophils can be reprogrammed to become powerful anticancer agents in tumors that are otherwise resistant to current immunotherapies," adds Josie Ursini-Siegel, principal investigator and director of the molecular oncology group in the cancer research axis at the LDI, and senior author of the study.
"This approach could open new avenues for the treatment of aggressive breast cancers, particularly triple-negative breast cancer, for which therapeutic options are currently limited due to the tumor's ability to evade the immune system. This represents considerable potential for patients with limited treatment options who urgently need new effective therapies."
The study highlights that TLR agonists increase NF-κB signaling in neutrophils, which enhances the production of secretory granules and components of the NADPH oxidase complex, necessary for a respiratory burst that triggers cytotoxic responses. At the same time, complex I inhibitors amplify this effect by potentiating the ability of neutrophils to undergo respiratory burst, leading to oxidative damage in breast cancer cells.
It is important to note that neutrophil depletion in experimental models abolished the antitumor effects, underscoring the critical role of these immune cells in the success of the therapy.
This dual therapeutic approach not only mobilizes neutrophils into the tumor microenvironment but also enhances their cytotoxic functions, offering a promising new therapeutic strategy for immunologically cold breast tumors that have so far evaded effective immunity-based treatments.
The research also sheds light on the importance of understanding the complex interactions between the tumor microenvironment and the immune system. By targeting key biological processes required for the survival of heterogeneous populations of cancer cells, researchers can develop more effective therapies that abrogate the activation of a pro-tumorigenic immune microenvironment and instead engage new modes of immune surveillance of the tumor.
"Our findings have significant implications for the development of new breast cancer treatments, especially for patients with limited options," says Ursini-Siegel. "They highlight the need for a multidimensional approach to cancer treatment that takes into account the complex interactions between the tumor and the immune system."
In conclusion, this research builds on the understanding that breast cancers often evade immune destruction through complex metabolic and inflammatory mechanisms, and it emphasizes targeting innate immune cells rather than relying solely on adaptive immunity. Although further research is needed to fully elucidate the mechanisms by which complex I inhibitors enhance neutrophil function, this study marks a significant advance in the field of precision oncology.