Abstract PR012: Unveiling the Immunoregulatory Role of Tumoral B7-H3 in Promoting the Immunosuppressive TME of Medulloblastoma
Kirsten Moziak, Daniel Weiser, Allison M. Martin, Xingxing ZangAbstract
Background:
Medulloblastoma (MB), the most common embryonal pediatric brain tumor, with a 30% rate of relapse, and relapsed tumors remain practically incurable. While immune checkpoint inhibition (ICI) stands as an alternative treatment, few trials have actually tested its application in MB. Current FDA-approved immune checkpoint inhibitors primarily rely on T-cell mediated anti-tumor responses. These ICIs may yield poor in MB due to its "cold" tumor microenvironment (TME), characterized by low expression of clinically targetable immune checkpoint molecules, a paucity of infiltrating T-cells, and an abundance of tumor-associated macrophages/microglia (TAMs). B7-H3 (CD276) is an immune checkpoint molecule with low protein expression in normal tissue and high protein expression in many cancers, including MB. B7-H3 expression correlates with poor prognosis in MB, however the mechanism by which tumoral B7-H3 mediates an immunosuppressive TME to promote a poor outcome is unclear. Tumoral B7-H3 has demonstrated the ability to polarize TAMs in other cancers. We hypothesize that tumoral B7-H3 skews MB TAMs towards an immunosuppressive state, and that these TAMs lead to T-cell dysfunction and exclusion.
Methods:
To test how B7-H3 on tumors affects the TME, we have lleveraged a novel syngeneic mouse cell line of aggressive MB developed by mentor that can be implanted into mice with intact immune systems, and created a knockout of B7-H3 in these cells using a CRISPR/Cas 9 lentivirus and sorted a heterogenous iteration of these cells into B7-H3+ and B7-H3KO clones. We implanted these clones into the cerebellum of C57BL/6J mice, collected survival, and analyzed their TME via IHC and flow cytometry. We also used these cells in co-cultures with macrophages and T cells to deduce the effect of tumoral B7-H3 expression on specific immune cell subsets.
Results:
We see that mice implanted with B7-H3KO tumors (N=15) have sitgnificantly increased survival compoared to those implanted with B7-H3+ tumors (N=14; p<0.0001). Preliminary data also suggests increased CD8 T cell infiltration in the tumors of B7-H3KO tumor-bearing mice. Additionally, macrophages co-cultured with tumor cells do demonstrate expression of immunosuppressive markers, Arg1 and CD206, but siginificantly fewer macrophages co-cultured with B7-H3KO cells express immunsupressive markers compared to those cultured with B7-H3+ tumors.
Conclusions:
Preliminary data suggests inhibiting B7-H3 may shift this cold TME, consisiting of few T cells and immunosupressive TAMs, towards a hot TME with more cytotoxic T cells, decreased immunosupresive TAMs, and increased survival. B7-H3 inhibition, therefore, may pivot the prospects of other T cell focused ICI, such as PD-1 inhibition. Our findings could completely change the course of disease for patients by providing a curative approach for relapsed patients. This research represents a key step forward towards informing therapeutic approaches in the management of immunosuppressed tumors.
Citation Format:
Kirsten Moziak, Daniel Weiser, Allison M. Martin, Xingxing Zang. Unveiling the Immunoregulatory Role of Tumoral B7-H3 in Promoting the Immunosuppressive TME of Medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr PR012.