A study from the Ludwig Institute for Cancer Research explains a mechanism by which melanoma tumors can resist cancer immunotherapy. The work appears in last week's Nature Communications.
"Immunotherapy has been delivering some impressive results, but only for a fraction of patients," says Benoit Van den Eynde, Director of Ludwig Brussels. "Now the million dollar question is, what can we do to improve the proportion of patients that respond to these treatments? There are a variety of mechanisms of immune resistance that operate in the tumor. This is what we are addressing in our studies."
To recapitulate the process of how a tumor arises, the response from the immune system and the tumor's escape, the researchers engineered a mouse to express a cancer-causing gene and a cancer antigen known as P1A, but only when given a particular drug. They then checked how different immunotherapies stood against the induced melanoma tumor, but none of them worked.
"To my great surprise, even injecting 10 million activated T cells specific to the P1A antigen did not affect tumor growth in this induced tumor model," says Van den Eynde. When the same induced cancer cells were transplanted into mice to generate tumors, the adoptive T cell therapy (ACT) invariably cleared the transplanted tumors.
The researchers were confused by the different results and wanted to find out why.
"We found that in the induced tumors, about half of the T cells were already apoptotic four days after ACT," says Van den Eynde. "This explained why they did not persist: The induced tumor behaves like a sink for these T cells. That does not happen in the transplanted tumors."
The study's team also compared the noncancerous cells present in the induced and transplanted tumors. They found a cell type called polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) were only in the induced tumors. These PMN-MDSCs also expressed high levels of a surface protein known as FAS-ligand, which induces T cell suicide when it binds its receptor on T cells. So the researchers depleted the PMN-MDSCs from the tumors or blocked the FAS-ligand binding to its receptor. By doing this, they were able to restore the effectiveness of the T cells to kill induced tumors.
"This is a novel mechanism by which these cells suppress immune responses in tumors," says Van den Eynde. "Targeting FAS-ligand could be a good adjunct therapy to boost the effects of immunotherapeutic drugs."