 <p class="lead" id="first">Ovarian cancer is a difficult to diagnose malignancy that is often caught at a more advanced stage. Treatments for this cancer have changed little over the past few decades, with surgery and chemotherapy being the most common therapeutic approaches. Immunotherapy, a type of treatment that activates a patient's immune system to target cancer cells, has been successful in many diseases but not ovarian cancer and it is unclear why.</p><p>Researchers at Moffitt Cancer Center want to improve their understanding of the immune environment in ovarian cancer in hopes of making immunotherapy an option for these patients. In a new study published in<em> Cancer Cell,</em> they report on key characteristics of immune cells in ovarian cancer and identify cell types important for mediating an immune response.</p><p>Checkpoint inhibitors are a specific type of immunotherapy that work by activating an immune cell called T cells. In order for checkpoint inhibitors to work, patients must have T cells that are ready to be activated in close proximity to tumor cells. Ovarian cancer is considered a type of tumor that should be impacted by checkpoint inhibitors because of T cell presence; yet clinical studies in ovarian cancer for these drugs have not been successful.</p><p>Moffitt researchers, led by Immunology Department Chair Jose Conejo-Garcia, M.D., Ph.D., wanted to determine whether ovarian cancer has the proper T cells to initiate an immune response and characterize the properties of the T cells present within ovarian cancer tumors. They performed a comprehensive analysis of ovarian cancer patient samples at the single-cell and tissue levels. They discovered that ovarian cancer is an immunogenic type of tumor that should be impacted by drugs that activate the immune system; however, immune activity against tumor cells is dependent on a small subset of immune cells.</p><p>The researcher team analyzed the types of T cells present in ovarian tumors and discovered that tissue-resident memory like T cells do a better job of recognizing tumor cells than T cells that are circulating and infiltrating the tumor. They also discovered that tissue-resident memory like T cells arise from circulating T cells and undergo a differentiation process into a tissue-resident memory stem cell that can generate T cells that actively target cancer cells. Some of these active T cells will eventually differentiate into an exhausted, inactivated state. The researchers confirmed that tissue-resident memory stem cells were important for anti-tumor immune activity by demonstrating that high numbers of them were associated with improved patient survival in ovarian cancer.</p><p>Interestingly, some of these lymphocytes show features of trogocytosis, a process where T cells take up a chunk of the membrane of target tumor cells. A trajectory of differentiation of tissue-resident memory T cells from stemness to irreversible exhaustion, in addition to evidence of trogocytic activity, identifies the T cells truly relevant to determine ovarian cancer patients' outcome.</p><p>These results demonstrate that ovarian cancer, despite resistance to existing immunotherapies, is indeed an immunogenic disease and provide a roadmap for the design of improved immunotherapy options, which could be applicable to other tumors with similar mutational burden.</p><p>This study was supported by the National Institutes of Health (R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758, R01CA184185, RO1CA262121, T32CA009140, P30CA076292) and the American Cancer Society.</p>