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Dissecting Regulatory Networks That Mediate Dendritic Cell Suppression

Periodic Reporting for period 2 - CANCER-DC (Dissecting Regulatory Networks That Mediate Dendritic Cell Suppression)

Reporting period: 2019-07-01 to 2020-12-31

Cancer is a major cause of illness and death all over the world. Surgeries, radiation, and chemotherapy were the main cancer treatments in the last century, but in the last decade, a new treatment has emerged, immunotherapy, and was shown to benefit cancer patients. The basic concept of immunotherapy is to “convince” the immune system to kill tumor cells. There are many contradicting factors that induce or inhibit immune response against tumors and cancer cells. The formation of a suppressive environment induced by cancer is considered a major cause for tumors' escape of immune cell killing. The suppressive environment is produced by many different cell types including fibroblasts endothelial cells, epithelial cells, and immune cells, that express immunosuppressive cytokines and receptors.
Following extensive basic research of the immune system and first successful results in melanoma patients, it was shown that manipulations of the immune system, and blocking the suppressive signals can be used to treat cancer. Since 2011, when FDA approval for a checkpoint blockade antibody, was received and shown to be effective, huge efforts were made to improve the immune response to cancer, and today immunotherapy is used as first-line therapy in some cancer types. It is important to note that immunotherapy is effective for some cancer types, for example, melanoma, lung cancer, but not in all the cancer types. In addition, also for these cancer types, only a portion of the patient responds.
We are interested to reveal and explore the suppressive signals that produce by aggressive cancer types such as ovarian and pancreatic cancer and to find new ways to manipulate the immune cells to fight cancer. We focus on dendritic cells that bridge between the two branches of the immune system, the innate immune and the adaptive immune systems, and extensively search new ways to manipulate them to fight cancer.
Since the start of the project, we made significant progress in all the objectives of the study and the first paper is now accepted to Nature Communication journal. 
We have profiled pancreatic cancer development from early lesion to tumor using single-cell RNA-seq including validation of the main genes using immunohistochemistry. In addition to the extensive mapping of the changes in epithelial cells, We created a roadmap of the immunoactivatory and immunosuppressive signals along the course of the disease. These suppressive signals affect immune cells including neutrophils, T cells, B cells, macrophages, and dendritic cells. Blocking the effect of the signals or manipulating the immune cells, can reverse the effect of the suppressive signals and induce the immune cells to kill malignant cells. Interestingly, we found that the suppressive signals emerge in a very early stage of the pre-malignant lesions before tumor formation. Thus, we could profile the changes in immune cells overtime at the single-cell level.
We have also found and profile a new sub-type of dendritic cell (DCs). This new subtype was found in the tissue but express markers of mature DCs and we are now farther investigated its function.  
We are now working on new methodologies for tumor profiles and expect to publish the new methods until the end of the ERC grant period.