Cancer immunotherapies such as drugs targeting the immune inhibitory molecules known as PD-1 and PD-L1 have shown benefit across a number of cancers. Unfortunately, in ovarian cancer, only a small fraction of patients responds to such treatments. It is thus necessary to identify the mechanisms that allow ovarian tumors to resist immunotherapy and to develop novel approaches that can target such mechanisms.
The biomarkers of response to immunotherapy in ovarian cancer remain unknown. Our preliminary data indicate that biomarkers that can predict response to PD-1 in other cancer types (such as high number of mutations or expression of a protein called PD-L1) appear not to work in ovarian cancer. In our studies we have found that mutations in genes encoding proteins that are involved in DNA remodeling (known as SWI/SNF complex proteins) seem to influence response to immunotherapy. The mechanisms underlying this effect are unknown. Understanding of such mechanisms may lead to a better selection of patients for clinical trials with immunotherapy and for development of drugs specifically targeting these pathways.
We hypothesize that changes in SWI/SNF genes in cancer lead to structural changes in the DNA that can lead to activation of pathways that promote or block recognition of cancer cells by the immune system.
To formally evaluate this, we have developed a number of mouse cancer cell lines that are either deleted for the specific SWI/SNF proteins or express them at high levels. Our preliminary data indicate that some of these changes can indeed influence recognition by the immune system and increase responses to PD-1 blockade in mice. Our research will aim to:
1.Characterize the mechanisms by which this immune recognition occurs
2.Using mouse models, determine whether drugs targeting chromatin remodeling, namely BET inhibitors, can improve responses to immunotherapy in cancers carrying such mutations.
The results of the study will also help us understand the mechanisms of response and resistance to immunotherapy and may help with selection of patients that are more appropriate for immunotherapy. In addition, the results of this work may lead to development of novel immune treatments for ovarian cancer and possibly other cancer types.