Targeting mechanisms of Siglec15-mediated immune evasion in hematologic malignancies
Novel therapeutic strategies are still needed for hematopoietic malignancies (HM), which are the most common cancers in children. Harnessing the potency of the immune system has great promise for some of these patients, but limitations in available approaches remain. Our long-term goal is to develop novel therapeutic strategies for HM based on a greater understanding of the mechanisms of immune evasion. The objective of this project is to investigate a novel therapeutic target for HM, Siglec15 (Sig15).
The central hypothesis of this project is that Sig15 is abnormally expressed in HM, contributes to immune evasion, and can be inhibited in leukemia and/or lymphoma cells to promote immune clearance. This hypothesis stems from our observations that inhibition of Sig15 prolongs survival in mice with leukemia with an intact immune system, but not in mice with an impaired immune system. Furthermore, Sig15 is expressed at higher levels in HM cells as compared to normal. We will test our hypothesis through the following specific aims: 1) Determine whether inhibition of Sig15 enhances immune-mediated clearance of malignant hematopoietic cells, 2) Determine whether and how Sig15 is overexpressed in malignant hematopoietic cells, and 3) Determine whether Sig15 activation/signaling is required for immune evasion of malignant hematopoietic cells. The project is innovative in that we have identified a novel role for Sig15 as an immune modulating molecule and therapeutic target in HM. The proposed work is significant because it will provide critical data for the design and justification of clinical trials targeting Sig15 in HM.