The study focuses on understanding why some cancer treatments that use the body's immune system (immunotherapy) don't work as well as they should. The researchers used two mouse models that were resistant despite a good influx of effective tumor-specific T cells to study how the environment within the tumor affects the response to immunotherapy. They found that a small group of immune cells called CD163hi macrophages, which are usually found at the edges of tumors, were responsible for the resistance to immunotherapy.

These CD163hi macrophages have anti-inflammatory properties and can turn off other immune cells that should be attacking the tumor. The researchers also discovered that targeting these macrophages with common therapies is difficult.

Oncode researcher Marit van Elsas, first author of the publication, explains: “By using two unique tumor models, we identified a small but discernible macrophage population of high CD163 expression to be responsible for both primary and secondary immunotherapy resistance. We show that these macrophages reside at the tumor invasive margin, where they negatively affect CD8+ T cells via different mechanisms, including heme oxygenase activity. Importantly, we also show that these macrophages are resistant to Csf1R-targeted therapies.”

Anti-inflammatory macrophages have been implicated to negatively impact (immuno)therapy outcome and Csf1R-targeted therapies have been suggested as a solution, but were met with disappointing clinical results. Van Elsas concludes: “In this research we show that targeting of macrophages by Csf1R therapies does not affect those subsets of M2-like macrophages with a strong negative impact on immunotherapy outcomes. By identifying the appropriate targets on the subsets of cells that cause therapy failure, such as CD163^hi macrophages, we can hopefully decrease primary and secondary immunotherapy resistance in patients. Via our Oncode Accelerator project, funded by KWF, we are continuing our research om this topic.”