The immune system removes transformed cells that give rise to cancer. For many years, the process that tumors use for shielding against the immune system was poorly defined. Now the factors that prevent tumors from being destroyed are being discovered. This is spurring new drugs to be made that kick-start immune cells to reject tumors. These new drugs, named immune ‘checkpoint’ inhibitors, are having a major impact on the treatment of patients with different cancers. These drugs disrupt tumor shielding to revive immune cells for combat and inspire hope that one-day patients may no longer need toxic chemotherapy. Although many patients respond well to immune therapy drugs, with time, the tumor can adapt and develop new tactics to outsmart immune cells. Now that more than 40% of cancer patients are candidates for immune therapy, drug resistance is becoming a key problem.
With colleagues at Vanderbilt University, we recently studied how resistance may develop in patients with melanoma, breast, and lung cancer. We found new factors that could cause tumor resistance, but might also be novel targets for immune therapy. In this proposal, we first plan to study these new targets in tumor samples from patients with resistance. Secondly, we will learn how they bind to tumor shielding factors and screen drugs that could block them. Finally, we will study these new immune therapy drugs in mouse models of cancer. We expect that this proof of concept study will introduce a new target for next stage development in early clinical trials.