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CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma
Kyle B Lupo1, Sandro Matosevic2,3
1Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA.
Abstract:
Natural killer (NK) cells are powerful immune effectors, modulating their anti-tumor function through a balance activating and inhibitor ligands on their cell surface. Though still emerging, cancer immunotherapies utilizing NK cells are proving promising as a modality for the treatment of a number of solid tumors, including glioblastoma (GBM) and other gliomas, but are often limited due to complex immunosuppression associated with the GBM tumor microenvironment which includes overexpression of inhibitory receptors on GBM cells. CD155, or poliovirus receptor (PVR), has recently emerged as a pro-tumorigenic antigen, overexpressed on GBM and contributing to increased GBM migration and aggressiveness. CD155 has also been established as an immunomodulatory receptor, able to both activate NK cells through interactions with CD226 (DNAM-1) and CD96 and inhibit them through interaction with TIGIT. However, NK cell TIGIT expression has been shown to be upregulated in cancer, establishing CD155 as a predominantly inhibitory receptor within the context of GBM and other solid tumors, and rendering it of interest as a potential target for antigen-specific NK cell-based immunotherapy. This review will explore the function of CD155 within GBM as it relates to tumor migration and NK cell immunoregulation, as well as pre-clinical and clinical targeting of CD155/TIGIT and the potential that this pathway holds for the development of emerging NK cell-based immunotherapies.
Insights
Natural killer (NK) cells combat tumors, but glioblastoma (GBM) creates an immunosuppressive environment. Targeting the CD155/TIGIT pathway offers a promising strategy for NK cell-based glioblastoma immunotherapy.
Area of Science:
- Immunology
- Oncology
- Neuro-oncology
Background:
- Natural killer (NK) cells are crucial immune effectors against tumors, regulating anti-tumor activity via cell surface ligands.
- Glioblastoma (GBM) presents a complex immunosuppressive tumor microenvironment, often limiting the efficacy of NK cell-based immunotherapies.
- CD155 (poliovirus receptor) is overexpressed in GBM, promoting tumor migration and aggressiveness, and modulates NK cell responses.
Purpose of the Study:
- To review the role of CD155 in GBM, focusing on its impact on tumor cell migration and NK cell immunoregulation.
- To explore the targeting of the CD155/TIGIT pathway in pre-clinical and clinical settings for GBM.
- To assess the potential of targeting CD155/TIGIT for developing novel NK cell-based immunotherapies against GBM.
Main Methods:
- Literature review of studies investigating CD155 function in GBM.
- Analysis of NK cell interactions with CD155 and its receptors (CD226, CD96, TIGIT).
- Examination of pre-clinical and clinical data on targeting the CD155/TIGIT axis.
Main Results:
- CD155 acts as a pro-tumorigenic antigen in GBM, enhancing tumor cell migration and aggressiveness.
- Within the GBM microenvironment, CD155 predominantly functions as an inhibitory receptor for NK cells via TIGIT.
- Upregulated TIGIT expression on NK cells in cancer contexts shifts CD155's role towards immune suppression.
Conclusions:
- The CD155/TIGIT pathway represents a significant target for overcoming GBM-induced immunosuppression.
- Targeting CD155 offers a potential strategy for enhancing NK cell-mediated anti-tumor immunity in GBM.
- Further development of CD155-targeted immunotherapies holds promise for treating glioblastoma and other solid tumors.
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