Colorectal cancer (CRC) retains its position as one of the most prevalent types of cancer with around 700,000 deaths per year worldwide. Treatments focused on altering the immune system have recently paved their way into oncology with clinical achievements seen in a broad spectrum of solid tumors. However, signals of activity in CRC are largely involving microsatellite instable tumors, leaving a great need for effective immunotherapy in the majority of patients. The biologica! complexity of the tumor microenvironment seems to be an obstacle for cancer immunotherapy, suggesting that a strategy to solely targeting tumor cells is inadequate to overwhelm the aggressively growing tumor in CRC. Cancer-associated fibroblasts (CAFs) represent the dominant constituents of the tumor stroma and play a critica! role in the proliferative and invasive behavior of CRC. Additionally, CAFs provide a physical barrier for the efficient delivery of systemic therapy to the tumor making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and cancer-restraining features. We have recently identified a phenotypically distinct subset of CAFs in invasive CRC specimens, marked by the expression of CD70, and associated with poor prognosis of the patient. Moreover, CD70-positive CAFs proved to stimulate tumor invasion and to promote immune escape by the accumulation of immune suppressive regulatory T-cells. lnterestingly, CD70 is totally absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs.
Based on our preliminary data, we hypothesize that targeting CD70-positive CAFs in CRC has a potential triple mode of action by enhancing anti-tumor immunity, eradicating a permissive niche for tumor invasion and increasing the efficacy of first-line chemotherapeutics. The primary objective of the proposed project is to find the ideal approach to deplete CD70-positive CAFs. The second objective is to design a combination strategy of CD70-targeted therapy with a first-line chemotherapeutic agent that elicits a potent anti-tumor immune response. The third objective is to identify potential bloodbased biomarkers for diagnosis and to monitor treatment response. Experiments will be performed in vitro under normoxic and hypoxic conditions and in vivo in an orthotopic syngeneic mouse model to identify the ideal timing and dosing of our combination strategy. This translational research project wil! lead to the launch of a phase 1/11 clinical trial in patients with advanced CRC with a grim prognosis of only 12 to 14 months. Since we have also found CD70 expression in the desmoplastic stroma of pancreatic cancer, this study will also pave the way to application in one of the most therapeutically resistant maliçinancies.