Combinatorial Epigenetic-Based Approach to Enhance Ovarian Cancer Immunotherapy
Abstract
Immunotherapy using immune checkpoint PD-1/PD-L1 inhibitors can elicit exceptional, long-term responses and even the potential for a cure in a subset of patients in multiple aggressive tumors, including melanoma, advanced renal cancer, and metastatic non-small lung cancer. However, ongoing immunotherapy clinical trials in ovarian cancer show a high rate of innate and acquired resistance to immunotherapy. This study addresses a major unmet need in the field of ovarian cancer, which is to understand the role of global methylation changes in innate and acquired resistance to immunotherapy. The investigative team will apply novel concepts, unique clinical biospecimens of ovarian cancer patients undergoing immunotherapy clinical trials at Dana Farber Cancer Institute, and clinically relevant, patient-derived model systems to tackle the challenging but important question of immunotherapy resistance. Successful completion of the proposed study will facilitate the development of novel strategies for epigenetic reprogramming in immunotherapy-resistant ovarian tumors. The proposed study aims to elucidate epigenetic mechanisms underlying the absence of response to immunotherapy in ovarian cancer. Growing evidence indicates that epigenetic events play key roles in ovarian cancer tumorigenesis and the development of a tumor phenotype resistant to therapy, including immunotherapy. Our research group has recently published multiple key studies that investigate a novel DNA methylation marker named 5hmC, a human genetic “tag” that can be turned ON or OFF by micro-environmental changes. Our results and others have now identified the 5hmC “tag” as a biomarker for the progression of aggressive tumors, including brain, bowel, skin, breast, lung, and ovarian cancer. Most importantly, we were able to develop treatments that reverse the methylation defects in ovarian cancer, block the growth of tumor cells, and increase survival in human tumor xenograft models. In this study, we now propose to explore 5-hmC as a key methylation aberration in intrinsic and acquired resistance to immunotherapy. Immunotherapy resistance is present in a large proportion of patients prior to starting treatment and is due to a low immune checkpoint inhibitor expression (PD-L1) and reduced T-cell infiltration in the solid tumors. DNA methylation is important in the regulation of PD-L1 expression and thus plays a major role in modulating responsiveness to PD1 inhibitor treatment. In addition, DNA methylation also plays a key role in cytotoxic T cell “exhaustion” and depletion associated with tumor progression. Furthermore, DNA methylation blocks the differentiation of CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) and their acquisition of effector function, which is critical for an efficient response to immunotherapy and inducing tumor cell death. Consequently, in parallel with evaluation of dynamic methylation levels, we plan to assess expression of biomarkers relevant for immunotherapy responses in tumors, stroma, tumor-infiltrating immune cells, and within the tumor microenvironment. All of the tumor and immune markers will be compared in patients prior to delivery of immunotherapy, early during delivery of immunotherapy, and at the completion of immunotherapy. Therapeutic response to PD-1 blockade will be determined by evaluating tumor apoptosis and infiltrating immune cells, including TILs and immunosuppressive cells present within the tumor microenvironment. Immunosuppressive cells enable tumor immune escape by inhibiting anti-tumor immune responses. We anticipate that composite markers, which include the testing of the global DNA methylation of tumor cells in addition to scoring PD-L1 expression and the frequency of TILs, will be a more accurate predictor of immunotherapy response and will improve clinical outcome. Preliminary melanoma clinical trial data suggest that analyzing biomarker levels early during delivery of immunotherapy is p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010342
Entities
People
- Daniela Dinulescu
Organizations
- United States Army