Discovered receptors used by tumors to reprogram macrophages

The research paves the way for the development of new therapeutic approaches to prevent the pro-tumoral transformation of macrophages, the main cells of innate immunity.

A study published in Nature Immunology has revealed a new mechanism through which tumors influence the functioning of innate immunity to their advantage: for the first time, the receptors regulating the pro-tumoral transformation of macrophages have been identified. These receptors are called “chemosensors” and are already known for their role in the olfactory system: preventing their activation by the tumor would constitute a new approach to immunotherapy based on innate immunity, a path that has so far been little explored.

The study, led by Diletta Di Mitri − Associate Professor at Humanitas University and Group Leader at Humanitas Research Hospital − was made possible with the support of the AIRC Foundation for Cancer Research and European funding from TRANSCAN.

Collaborators included Logan Walsh’s group from McGill University in Canada, and clinicians Massimo Lazzeri, Paolo Casale, and Piergiuseppe Colombo from the Urology and Pathology departments at Humanitas Research Hospital, who provided prostate cancer biopsies to validate the discovery in a clinical context.

“This research has allowed us to make a fundamental step forward in understanding how tumors modulate innate immunity,” explains Diletta Di Mitri. “Identifying the main communication channel through which macrophages are manipulated in the tumor microenvironment opens the way to the development of new therapeutic approaches.”

Chemosensors and macrophage recruitment

Chemosensors are proteins traditionally studied in the nervous system, particularly for their role in smell. However, the study revealed for the first time that these receptors are also involved in the activation of macrophages in the tumor.

“Chemosensors respond to the presence of lipid molecules, such as palmitic acid, abundant in the tumor microenvironment. The activation of these receptors leads to the transformation of macrophages into a pro-tumoral phenotype that promotes cancer growth and metastasis,” explains Giulia Marelli, first author of the study − Assistant Professor at Humanitas University, and researcher in Di Mitri’s group.

New immunotherapy approaches: targeting chemosensors to re-educate macrophages

The discovery that chemosensors regulate macrophage behavior in tumors has significant therapeutic implications, as demonstrated by the fact that the elimination of these receptors in the lab led to disease regression and increased infiltration of tumor-reactive T cells.

“These results suggest that targeting these receptors could alter the tumor microenvironment in a way that favors the anti-tumor immune response, potentially enhancing the effectiveness of immunotherapies already in use − immune checkpoint inhibitors, which work by promoting the action of T lymphocytes against cancer,” concludes Diletta Di Mitri.