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Training phagocytes to destroy tumors

Researchers at the University of Turku have developed an immunotherapeutic antibody therapy that re-educates macrophages to activate passivated cytotoxic T cells to kill cancer.

In collaboration with Professor of Immunology Sirpa Jalkanen, Academy Research Fellow Maija Hollmén’s research group have investigated the possibility to utilize tumor-associated macrophages to increase the immunological detection and killing of cancer cells. The antibody-therapy that they have developed has shown to prevent the growth of tumors in several mouse models, and the researchers found that blocking a Clever-1 function on macrophages activated the immune system and was highly effective in inhibiting cancer progression. Clever-1 is a cell surface receptor expressed mainly by endothelial cells and monocytes/macrophages and it has previously been shown to control cell-mediated immunity.

Inhibiting Clever-1 functions

By inhibiting Clever-1 functions, tumor-associated macrophages that normally impair adaptive immune cell activation, such as cancer cell killing by cytotoxic T cells, were managed to be re-educated so that they had increased ability to present antigen and secrete pro-inflammatory cytokines leading to increased activation of killer T cells.

“Macrophages are an ideal drug development target as they express several molecules that can be activated or impaired to transfer the macrophages into cells that destroy cancer. In itself, this would increase beneficial inflammation in the tumor microenvironment, which would improve the efficiency of immune checkpoint inhibitors in those patients whose response is weak due to lack of tumor-specific T cell activation,” says Doctoral Candidate Miro Viitala, the main author of the study, published in the journal Clinical Cancer Research.

Every cancer is different

The antibody therapy targeting Clever-1 worked in the studied tumor mouse models as efficiently as the PD-1 antibody therapy that is in clinical use. The PD-1 antibody maintains the functionality of the killer T cells. It is notable that the Clever-1 antibody therapy targeting macrophages also increased the activity of the killer T cells efficiently, state the researchers. In certain mouse models of cancer, a combination of anti-Clever-1 and anti-PD-1 therapies prevented tumor growth and formation of metastases more effectively than either treatment alone.

“Every cancer is different. Therefore, it is important to explore the types of cancer where Clever-1 antibody therapy most effectively works on and to find biomarkers that can be used to identify beforehand the patients that will benefit the most from this kind of therapy,” says Viitala.

Source: Turku University