Role of Macrophage-secreted BIGH3 in Tumor Immunity

Project summary

Ovarian cancer (OvCa) is the deadliest US gynecologic malignancy with a clear need for novel therapeutic approaches. Immunotherapy, a class of treatments that restores the patient’s immune system to recognize and kill cancer cells, is one promising approach to improve the outcome of OvCa patients. While current immune therapies work very well in some types of cancer, they show limited clinical efficacy in women with ovarian cancer with response rates of 10–15%. One reason for these disappointing results may be OvCa’s unique tumor microenvironment (TME). We recently demonstrated a population of cells in the OvCa TME, known as a carcinoma associated mesenchymal stem cells (CA-MSCs), are driving the poor response to immune therapy. CA-MSC create dense scar tissue around islands of cancer cells, and recruit populations of immune-suppressing macrophages to the scar tissue. This macrophage laden scar tissue prevents cancer fighting immune cells from entering the tumor. Importantly we found that targeting this CA-MSC/macrophage axis can overcome this immune-suppressive barrier and allow immunotherapy mediated tumor eradication. These studies suggested a poorly studied macrophage factor, BIGH3, may be driving the immune-suppression of CA-MSCs. We found that BIGH3 directly inactivates the anti-cancer activity of a critical population of cells know as NK cells. Furthermore, high BIGH3 expression is associated with shortened patient surivival and poor response to immune therapy. We hypothesize that BIGH3 is a critical suppressor of anti-tumor immunity in ovarian cancer, restricting the entry anti-tumor immune cells into the tumor, thereby inhibiting the response to immune therapy. As an extension of this, we postulate that blocking BIGH3, will be an important therapeutic approach to enhance the efficacy of anti-tumor immune therapies. To test our hypothesis, we propose the following aims: Specific Aim (1): To determine the molecular mechanisms by which BIGH3, secreted by monocytes and macrophages, blocks the tumor killing activities of NK cells. Specific Aim (2): To determine if therapeutics targeting BIGH3 will restore an active anti-tumor immune response. We will develop a new antibody therapy targeting BIGH3 and determine if BIGH3 blocking antibody will act as an adjuvant to current immune therapeutic approaches. IMPACT: Based on the success of the first three years of support for our work, we will initiate a new clinical trial to improve ovarian cancer patient response to immune therapy (planned to start spring 2022).These new studies studies will generate a new putative therapeutic antibody targeting BIGH3 as a critical new target to enhance immune therapy. If successful, our studies will add to ongoing approach to improve the benefits of immune therapy for ovarian cancer patients.