Investigator
University Of Massachusetts Chan Medical School
Transforming treatment paradigms: Focus on personalized medicine for high‐grade serous ovarian cancer
AbstractHigh‐grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of all ovarian cancer cases and contributing significantly to the high mortality rates associated with this disease. Because of the asymptomatic nature of early stage disease, most patients are diagnosed at advanced stages when the cancer has already spread into the abdominal cavity, requiring complex and intensive surgical and chemotherapeutic interventions followed by maintenance therapies. Although a minority of cases are associated with well defined genetic syndromes, specific risk factors and a clear etiology in many cases remain elusive. HGSOC tumors are characterized by a high frequency of somatic gene copy number alterations, often associated with defects in homologous recombination repair of DNA. All attempts to introduce an effective screening for HGSOC to date have been unsuccessful. This review elucidates the complexities surrounding HGSOC and encompasses its etiology, epidemiology, classification, pathogenesis, and the current array of treatment strategies. Understanding molecular underpinnings is crucial for the development of targeted therapies and personalized multimodal treatment approaches in centralized therapeutic structures. This review also examines the importance of the tumor microenvironment. In addition, the authors' objective is to underscore the critical importance of placing the patient's perspective and diversity at the forefront of therapeutic strategies, thereby fostering a genuinely participatory decision‐making process and ultimately improving patient quality of life.
Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer
High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.
