How does prostate cancer escape the surveillance of the patient's immune system? Metastatic castration-resistant prostate cancer is the terminal stage of prostate cancer. After years of being poisoned by anti-tumor drugs and of being attacked by the immune system, the cancer at last became resistant. At this point, cancer cells are out of control. They will spread all over the body and ultimately kill the patient. Surely, the question of how the cancer cells had to change in order to become so resistant is at the forefront of prostate cancer research. Countless research teams try to come up with new drugs or try to explain why the old drugs don't work. However, surprisingly few ask how the prostate cancer was able to outsmart the patient's immune system. If we knew this, we could decide when to use a special class of drugs that boost the immune system or maybe even we could think of a completely new drug that makes the cancer vulnerable again.

Because very little is known about how cancers become resistant to the immune system, our plan is to begin by looking at a large number of metastatic tumors. We will compile all the different ways by which immune systems attack tumors and by which tumors evade the immune systems. When completed, this compendium will be the first comprehensive analysis of the role of immunity in metastatic prostate cancer and the necessary knowledge base for further research. In this research, we will analyze huge genomic data sets (billions of data points). Most of this work requires advanced algorithms and clusters of computers, which is why an important aspect of our study is the validation of computational results with further experiments. What our team has learned so far is that most metastatic tumors completely stop producing the "major histocompatibility complex"; without these molecules, the cancer becomes essentially invisible to the part of the immune system that learns (or adapts) to recognize and respond to threats. Based on all we know, boosting the adaptive immune system in these patients will not overcome resistance. On the other hand, we have found that some tumors were actively attacked by the killer cells of the adaptive immune system. For those patients, even a small boost to immunity may tip the scales and improve their lives.

Our goal is to turn discoveries like these into clinical tests. The test results will tell the doctor the immune status of a metastatic tumor, and he or she will have a better idea how the patient's disease is likely to develop. This in turn will allow the doctor and patient to make better-informed decisions. Here at the Michigan Center for Translational Pathology, we are committed to rapidly translate scientific discoveries from research to clinic. We have had success in the development of novel clinical tests for a number of cancers with a strong emphasis on prostate cancer. Not all research findings can be developed into a novel drug or test, but we understand what it takes. This is why a significant portion of this research is concerned with the critical technical aspects of every clinical assay, such as validity, to mitigate potential risks to the patient.

If we achieve our aims, within a few years patients with metastatic prostate cancer will know their tumors immune status that will guide their therapy. In fact, as part of a trial, we are reporting preliminary immune status information to very select patients in the "MI-Oncoseq" precision oncology program at the University of Michigan. However, the ultimate goal is to make tumor immune testing widely useful and available for all.