Abstract Diffuse midline glioma (DMG) with histone H3 lysine 27-to-methionine (H3K27M) mutation is a universally fatal pediatric malignancy. While radiotherapy is standard-of-care, nearly all patients recur in the radiation field, underscoring the need for new radiation (RT) therapeutic combinations. A key immunomodulatory effect of RT is to augment immune checkpoint expression including PD-L1/2. In DMG tumors, however, the PD-1/PD-L1 checkpoint has marginal expression that is consistent with a lack of clinical benefit to PD-1/PD-L1-based immunotherapies with radiotherapy. Importantly, another B7 superfamily member B7-H3 (CD276) shows uniformly and highly tumor-selective expression relative to other known immune checkpoints. We recently found that B7-H3 is dispensable for DMG tumor growth in immunodeficient NSG mice, but B7-H3 deletion significantly constrained tumor growth and extended overall survival with long-term survivors demonstrating complete responses, supporting that B7-H3 is a bona fide DMG-specific immune checkpoint. Rechallenge experiments showed that the long-term survivors, but not naive mice, were able to reject B7-H3+ DMG tumor cells, indicating the generation of immune memory. Additionally, B7-H3 cell surface levels were further enhanced in human DMG cells treated with RT in a dose-dependent manner. This induction was largely abrogated by inhibiting NF-κB activity, which is consistent with a potential NF-κB (p65/RelA) binding motif in the human B7-H3 promoter region. To explore the therapeutic potential of B7-H3, we utilized enoblituzumab, a human B7-H3 blocking antibody currently in clinical development, and found that B7-H3 blockade further promoted natural killer (NK) cell-mediated lysis of H3K27M mutant DMG cells following treatment with RT. Taken together, our work demonstrates that B7-H3 is a targetable immune checkpoint in DMG cells that is further induced after RT, supporting the potential for improved therapeutic strategies combining RT and B7-H3 blockade in DMG, a disease of highest unmet clinical need.
Li et al. (Fri,) studied this question.