How can myeloma cells evade immune surveillance?
Our study is to find out whether and how generation of adenosine in the bone marrow contributes to the suppression of myeloma-specific immune response, and whether this is a possibility to help these myeloma-specific immune cells recover from suppression when reducing adenosine in bone marrow.We found that the adenosine level from bone marrow is much higher in bone marrow cancer patients compared to healthy people. So we studied why this happens and what is the influence of the high adenosine level to patients. First, we checked the CD39 protein on the surface of cancer plasma cells, and we found the various expression. CD39 is an essential enzyme which converts ATP to AMP, then another essential enzyme-CD73, converts AMP to adenosine, that is how adenosine generated. Second, we checked the CD73 expression on the surface of bone marrow cells, and we found that bone marrow stromal cells highly express this enzyme. Because of the cell death in bone marrow of patients, there is more ATP, so if there is also more CD39 and CD73, then it could be one of the reasons that adenosine level increases. Third, we checked the whether these two enzymes work. So we put cancer plasma cells and ATP together, found that these cancer cells can convert ATP to AMP, but can not do this in the presence of POM-1, the inhibitor of CD39, which means CD39 on cancer plasma cells is functional. We also checked the functionality of CD73. We put stromal cells and AMP together, and found that stromal cells could convert AMP to adenosine, but can not do this in the presence of CD73 inhibitor, which means CD73 on stromal cells is functional. Then, we put cancer plasma cells, stromal cells together with ATP, found that they can co-work to generate adenosine. So this may explain how high level of adenosine generates in bone marrow. Next, we want to know what happens if the patient has higher adenosine level in the bone marrow. In order to investigate this, we take T cells out from patient's bone marrow, and culture these T cells with adenosine. We found that high level of adenosine can suppress the proliferation of T cells. On the other hand, we use cancer plasma cells, stromal cells and ATP instead of adenosine, and also found the same results, which is , these adenosine-generating cells can also suppress T cells. Then, we want too help these T cells recover from the suppression induced by adenosine, because we need these T cells to fight cancer cells, not just stand there. So we add inhibitor of CD39 and CD73 to stop the generation of adenosine, and it works. So there might be a way to help these T cells and they could do a better job to fight bone marrow cancer.
For fighting against Multiple Myeloma, which is a cancer has tumor cells grow in bone marrow, we want to wake up our immune army. Our immune army is supposed to destroy the cancer cells, but it fails because of some suppressive commands in our body. So find out these suppressive commands and weaken them to help our immune army wake up.That's what I am studying on now.In order to develop an efficient immunotherapy for Multiple Myeloma(MM), we need to understand whether and how the immune response recognize and control the tumor in the Bone marrow environment. We choose one possible reason which maybe responsible for this immune suppression in Multiple Myeloma --- the upregulation of adenosine(ADO) in bone marrow microenvironment. Tumors may use this mechanizm to subvert immune system. Many tumors and tumor-infiltrating cells upregulate CD39 and CD73, which leads to adenosine-mediated T suppression. Immune responses to myeloma cells are believed to take place in bone marrow, so manipulation of the immune response at that site could be important to reject tumor cells. The aim of our study is to determinate whether and how generation of adenosine from extra-cellular ATP in the bone marrow contributes to suppression of myeloma-specific immune response, and to investigate whether blocking ectonuclease activity or inhibiting ADOR on T cells could induce a myeloma specific immune response capable of rejecting the tumor. We have found that ADO/INO/AMP are higher in MM patients than normal, and MM patients have more CD39+ plasma cells which means they may have higher ability to produce ADO. We also found that some MM cell lines express a lot CD39, and these cell lines can convert ATP to AMP quickly. However, they can not convert AMP to ADO because the lack of CD73. In bone marrow, a lot of cells express CD73, like some B cells, mesenchymal stem cells and stromal cells. Adding these cells to MM cell lines can produce a lot ADO, which means this system may release high level of ADO. Then, we found if we co-culture T cells with these MM cell lines and stromal cells, as a result of upregulation of ADO, T cells are suppressed. Block the receptors on T cells, this suppression disappears. We need to repeat these experiments and add more data. As far as now, this project goes well and we need more time to collect enough data.