Translating Science into Survival
Exciting findings about immune cells that serve two masters: humans and tumors. Findings form the ICIC meeting
When we think of our immune system, we imagine legions of soldiers with different skills protecting us from harm. But in certain situations, some immune cells are more foe than friend. Myeloid-derived suppressor cells (MDSCs), which regulate immune responses and tissue repair in healthy individuals, is one example. They can also rapidly expand during cancer and play an important role in tumorigenesis.
In cancer, MDSCs cause suppression of various immune cells in the tumor microenvironment, mainly T cells, but also natural killer cells, and B cells. They aggressively promote tumor angiogenesis, tumor cell invasion, and migration.
In preclinical models the accumulation of MDSCs in the lung is seen two days before lung metastases are detectable. The accumulation of MDSCs in patients is negatively correlated with overall survival as well as sensitivity towards checkpoint inhibitors, which work by inhibiting proteins on immune cells that prevent our immune system from fighting cancer. In these situations, MDSCs are thought to limit the effects of immunotherapy.
There are already three ways to target MDSCs. You can kill them with cancer agents like 5FU and gemcitabine but the specificity of these drugs are limited. You can also inhibit their function with PDE-5 inhibitors or differentiate them into more mature cells using the therapeutic drugs ATRA and Sunitinib.
Scientists have not had much luck minimizing the nasty effects of MDSCs, but a completely new strategy, discussed at the International Cancer Immunotherapy Conference, could potentially change those odds.
Dmitry Gabrilovich from The Wistar Institute—one of several investigators who coined the term myeloid derived suppressor cell years ago—found that it may be possible to regulate MDSCs by controlling a key protein axis central to the growth of tumors. The axis consists of two players: a colony-stimulating fibroblast 1 (CSF1) protein produced by tumor cells and a CSF1 receptor produced by cancer-associated fibroblasts. Tumors exploit the axis to keep their cells from aging and dying prematurely.
Previous studies have already showed that CSF1 can recruit MDSCs to the tumor site, but Gabrilovich and his team also recently showed that the CSF1 protein is, as well, regulated by a negative feedback loop. Thus, the recruitment of MDSC via the CSF1 axis leads to down regulation of CSF1 production to ensure the balance (homeostasis) of the system.
The work by Gabrilovich’s lab also showed that the CSF1 receptor can modulate MDSC recruitment. If CSF1R expression is low MDSC infiltration is low. Until now, everyone thought that MDSCs proliferate in the tumor, but Gabrilovich’s group showed that the cells were recruited outside of the tumor. This is obviously bad for the patient but good for the tumor. However, if you regulate MDSCs via the CSF1 axis you do not block proliferation of MDSCs but you do block the recruitment of the MDSCs to the tumor.
Ultimately, Gabrilovich was able to demonstrate that you can decrease the infiltration of MDSCs in the tumor using an antibody that inhibits a protein selectively expressed in many solid tumors.
Another interesting talk, this one by Sjoerd van der Burg at Leiden University Medical Center, looked at combining a drug that modulates myeloid cells with a therapeutic vaccine in cervical cancers cause by the human papilloma virus. His work found that CSF1 inhibitors selectively inhibited MDSCs.
Unfortunately, Gabrilovich has found that while CSF1 inhibitors selectively inhibit MDSCs, the inhibitors don’t work in humans. Why is the big question? Gabrilovich says this might be due to the negative feedback loop mentioned earlier. Furthermore, one subgroup of MDSCs were killed but another subgroup was actually enhanced by the inhibitors.
So it appears to be a vicious circle. The goal moving forward is to try and find other players in the signaling cascade which could be combined with CSF1 inhibitors, thereby preventing the detours MDSC are taking to suppress the body's fight against cancer.