Targeting prosaposin (pSAP) to dendritic cells as novel cancer immunotherapy
Background
Antigen-specific T cell responses are central to protection against cancer. Abundance and proper function of immune cells, including lymphocytes and antigen-presenting cells such as dendric cells (DCs), at the tumor site are vital for effective immunity and control of cancer growth. Harnessing these immunological mechanisms, such as T cells, to target tumor cells has advanced the development of modern cancer therapies. Effective T cell activation relies on their interaction with antigen-presenting cells like dendritic cells to help initiate and sustain immune responses in the cancer environment. However, tumors develop strategies to evade immunity by suppressing antigen presentation which hinders effective cancer treatment. Current therapeutic options, such as immune checkpoint blockade, aim at reinvigorating exhausted T cells to augment anti-tumor responses. However, these boosted T lymphocytes need to encounter their respective antigens in order to deploy their functions in a tumor-specific manner. Because of this, there is an urgent need to develop a safer and more powerful strategy to improve cancer immunotherapy.
Technology Overview
Boston Children’s Hospital researchers have discovered that targeting prosaposin (pSAP) and restoring its function can overcome the immunosuppressive effects of tumors. Specifically, delivering recombinant pSAP to dendritic cells (DCs) improves antigen presentation and enhances anti-tumor immunity, highlighting a potential therapeutic approach to restore effective immune responses against cancer.
Using in vivo mouse models and functional assays, the researchers found that:
- pSAP is essential for tumor immunity, and pSAP deficiency leads to increased tumor size, reduced antigen processing and presentation, a lower frequency of tumor-infiltrating T cells, and diminished cytokine production.
- pSAP is able to rescue T cell activation in melanoma patients, significantly boosting IFN-γ production and increasing the frequency of tumor antigen-specific T cells.
- Reconstitution of tumor DCs with recombinant pSAP provides protection against cancer by significantly enhancing antigen presentation, frequency of IFN-γ-producing, antigen-specific T cells at the tumor site. Notably, this method could rescue immune suppression in immunological active tumor microenvironment and immunologically cold tumors.
Applications
- Improved cancer vaccines with enhanced antigen presentation and delivery
- Cancer immunotherapy synergistically combined with immune checkpoint inhibitors
- Adoptive T cell therapy with engineered T cells to recognize and attack tumor cells
- Biomarker development by using pSAP as the efficacy of antigen presentation in tumors
- Preclinical research exploring new methods to boost immune response against various forms of cancer microenvironments
Advantages
- Increased efficacy of immunotherapies
- Performed pleiotropic effects on systemic inflammation and immunomodulation
- Synergistic effects with existing cancer therapies
- High potential to expand the therapeutic efficacy towards various types of cancers and potentially in other diseases where antigen presentation is a critical factor.
Publications
- Sharma P, Zhang X, Ly K, Kim JH, Wan Q, Kim J, Lou M, Kain L, Teyton L, Winau F. Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape. Science. 2024 Jan 12;383(6679):190-200. doi: 10.1126/science.adg1955. Epub 2024 Jan 11. PMID: 38207022.
- Florian Winau, Pankaj Sharma. (2023). Methods and compositions for enhanced antigen presentation in the tumor microenvironment (US patent WO2023240215A1).
