The study shows how certain macrophages dampen antitumor immunity

A study by Ludwig Cancer Research adds to growing evidence that immune cells known as macrophages that inhabit the body cavities that house our vital organs can help tumor growth by distracting CD8 + T cells that kill them. cancer of the immune system.

Informed in the current number of Cancer cell and led by researchers Ludwig Taha Merghoub and Jedd Wolchok at the Sloan Kettering Memorial (MSK) and Charles Rudin of MSK, the study shows that cavity-Resident macrophages express high levels of Tim-4, a phosphatidylserine (PS) receptor, a molecule they found surprisingly on the surface of highly activated, cytotoxic and proliferative CD8 + T cells.

“We believe that T cells that infiltrate the peritoneal cavity can be distracted by interacting with macrophages that express Tim-4,” said study lead author Andrew Chow, assistant physician at Ludwig Collaborative. MSK Laboratory.

Researchers also show that blocking Tim-4 in mouse cancer models can prevent this distracting interaction and increase the effectiveness of immunotherapies.

“I believe that in patients presenting with these serous cavity macrophages that express high levels of Tim-4, blocking Tim-4 will make immunity-based therapies more effective,” said Merghoub, co-director of the Col. laboratory Ludwig of MSK.

Just as people living in different cities may have different customs or accents, the macrophages in our body may adopt specialized functions and respond to disease differently depending on the tissue they inhabit. Scientists are increasingly interested in these localized responses, as the activities of macrophages can influence the recovery from a disease or injury and the responses therapy.

Merghoub, Wolchok, Rudin, Chow, and colleagues began exploring the role of macrophages in tumor immunosuppression after finding that cancer patients with lesions in the pleural and peritoneal cavities — which house the lungs and organs of the brain. gastrointestinal tract, respectively — were significantly less sensitive to immune checkpoint blocking therapy, which stimulates a CD8 + T cell attack on tumors.

“That told us there was something immunosuppressive in those cavities, so we went looking for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages that express high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also show a strong Tim-4 signal.

Therefore, the researchers suspected that macrophages residing in the cavity could affect the antitumor activity of CD8 + T cells through the actions of Tim-4.

These suspicions were partially justified when the researchers analyzed the cavity macrophages of patients with human lung cancer and found that although Tim-4 levels varied between individuals, those with higher receptor levels tended to have a reduced presence of CD8 + T cells responding to the tumor.

Based on these observations, the researchers explored whether Tim-4 blockade would improve the efficacy of PD-1 blockade therapies in a preclinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best protection against the tumor when you block both molecules,” Chow said.

Although Tim-4 blockade alone did not reduce the number of tumors or improve the survival of mice, it did improve the tumor protection provided by the PD-1 blocker and increased the number of cells. CD8 + T cells peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T cell therapy, in which tumor-targeted T cells are isolated and selectively cultured in a laboratory before being re-treated. infuse the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to enhance immunotherapy, regardless of whether you are trying to increase your immune response by immune checkpoint blockade therapy or by adoptive T cell therapy.” , said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of landscapes immune to and around tumors. “In the same way that we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile tumor immune landscapes and customize immunity-based therapies based on these studies, ”he said.