Tumors Discovered to Have Two Levels of Protection Against the Immune System

Tumors Discovered to Have Two Levels of Protection Against the Immune System

Researchers at Babraham Institute have demonstrated certain tumors have two processes that provide protection against the immune system. While it is possible to knock out either of those protective mechanisms, doing so results in the other going into overdrive.

Even when the immune system is fully functional, and tumors are recognized as cancerous and the immune system is capable of killing cancer cells, tumors continue to grow.

Tumors can hijack certain cells in the immune system to create an environment where they can continue to grow. They protect against anti-tumor elements by recruiting tumor-assisted macrophages (TAMS) and Foxp3+ T regulatory cells (Tregs).

The researchers explain in their paper, “Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance.” The researchers showed that when they inhibited the recruitment of TAMS – through genetic ablation of colony-stimulating factor 1 (CSF1) – there was a compensatory increase in recruitment of Foxp3+ Treg cells. There was an increase in CD8+ T cell attack on tumors, but this was largely negated by the Foxp3+ Treg cell protective mechanism. The same was true when Foxp3+ Treg cell recruitment was blocked.

Treatments targeting TAMs are currently being investigated in clinical trials, although the initial results have not been as promising as hoped. This new research provides clues as to why. The inhibition of the action of Treg cells using a PI3Kδ inhibitor has been approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin lymphoma (NHL), although it has yet to be established whether the treatment will be effective on solid tumors. The research suggests that the Treg cell inhibition may not be effective for the treatment of solid tumors without also blocking the recruitment of TAMs.

The research suggests new cancer immunotherapies would need to knock out both protective mechanisms to allow the immune system to attack the tumors. The researchers were able to demonstrate in a mouse model that blocking both mechanisms resulted in almost complete tumor rejection, with half of the mice in the study becoming completely tumor free when both mechanisms were blocked.

“Taken together, our findings provide a convincing rationale for assessing the clinical value of combinatorial therapies targeting the CSF1 receptor and PI3Kδ,” said David Gyori, Ph.D., first author on the paper.

The study, Compensation between CSF1R+ Macrophages and Foxp3+ Treg Cells Drives Resistance to Tumor Immunotherapy – was recently published in the journal JCI Insight.

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