A Novel Immune Checkpoint Pathway in Human Prostate Cancer
Abstract
Prostate cancer ranks second to lung cancer in terms of annual mortality among men in the United States. The mainstay of therapy for advanced prostate cancer, unchanged since 1941, continues to be palliative androgen deprivation. As such, more effective treatments of prostate cancer are urgently needed. In this respect, immunotherapy could offer an important alternative or adjunct to current therapy. The B7 family and their receptor CD28 family molecules are the major immune checkpoints to regulate immune cells activation and function. We and others have discovered additional members of the B7/CD28 families. The discovery of immune checkpoint pathways and the subsequent development of therapeutics that target these pathways have marked a revolution in the treatment of cancer. However, one of the biggest challenges is that the majority of cancer patients, particularly human prostate cancer, do not respond to current FDA-approved immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 because human prostate cancer rarely expresses ligands for PD-1 or CTLA-4. Therefore, discovery of new immune checkpoints and development of new strategies targeting additional immune checkpoints are keys to improving the immunotherapy. Very recently, we discovered a new human immune checkpoint pathway of HHLA2-KIR3DL3. Furthermore, we have recently conducted the first comprehensive study to evaluate the expression pattern and clinical significance of HHLA2 in 239 prostate cancer patients from two independent cohorts. We revealed that HHLA2 protein is not expressed in normal prostates, but is highly expressed in more than 68% of prostate cancer samples, and that HHLA2 is significantly associated with disease stage, metastasis, and poor survival. These new studies with novel findings strongly suggest that targeting KIR3DL3-HHLA2 is a promising strategy and potentially has high impact in clinical management of prostate cancer, which represents novel checkpoint inhibitors that target outside the PD-1/PD-L1 and CTLA-4 pathways. We have generated a number of important new tools that provide us with unique opportunities to develop new prostate cancer immunotherapeutic strategies. The results from this proposal will have a significant impact on the concepts or methods that drive the field and make an original contribution to the goal of cure of prostate cancer. The proposed research is significant and novel because it is anticipated to develop new therapeutic interventions that can produce potent anti-tumor effects, which will aid the growing numbers of prostate cancer patients. In addition, it is expected that the proposed research will fundamentally advance the field of new immune checkpoints in cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210376
Entities
People
- Xingxing Zang
Organizations
- Albert Einstein College of Medicine
- United States Army