2026-10-05 ペンシルベニア州立大学（Penn State）
＜関連情報＞
- https://www.psu.edu/news/medicine/story/making-pediatric-cancer-more-visible-boosts-immunotherapy-response
- https://www.tandfonline.com/doi/full/10.1080/15548627.2026.2717948
IPIK3C3/VPS34の阻害は神経芽腫における抗GD2免疫療法の効果を高める nhibiting PIK3C3/VPS34 enhances anti-GD2 immunotherapy in neuroblastoma
Jiawen Zhang,Xiaoming Liu,Longgui Chen,Todd D. Schell,Giselle Saulnier Sholler,Vladimir Spiegelman,…
Autophagy Published:20 Aug 2026
DOI:https://doi.org/10.1080/15548627.2026.2717948
ABSTRACT
Anti-GD2 immunotherapy has improved survival in children with high-risk neuroblastoma, yet relapse and refractory disease remain major challenges, underscoring the need for strategies that extend therapeutic benefit. We investigated whether inhibition of PIK3C3/VPS34, a class III PtdIns3K that regulates autophagy and endosomal trafficking, could potentiate anti-GD2 therapy. Inducible PIK3C3/VPS34 knockdown induced apoptosis, impaired spheroid growth, and suppressed tumor progression. Notably, PIK3C3/VPS34 depletion enhanced anti-GD2 antibody-driven NK cell cytotoxicity and increased tumor cell-surface GD2 expression. In vivo, combined PIK3C3/VPS34 inhibition and anti-GD2 therapy achieved durable tumor suppression, which was associated with increased infiltration of NK cells and T cells, enhanced T-cell activation, reduced immunosuppressive myeloid populations, enhanced pro-inflammatory macrophage polarization, and elevated production of immune-recruiting chemokines. Pharmacological PIK3C3/VPS34 inhibition recapitulated the effects of genetic depletion, inducing neuroblastoma cell death and enhancing anti-GD2 antibody-dependent NK cell cytotoxicity in vitro. Enhanced NK cell-mediated killing was associated with marked enrichment of GD2 at the tumor cell surface. PIK3C3/VPS34 inhibition caused a disproportionate increase in surface relative to total cellular GD2 levels, while combined inhibition of PIK3C3/VPS34 and lysosomal function resulted in additional GD2 accumulation, supporting a role for endolysosomal processing in controlling GD2 abundance. Together, these findings demonstrate that PIK3C3/VPS34 inhibition enhances the efficacy of anti-GD2 immunotherapy through complementary tumor-intrinsic and immune-mediated mechanisms, including direct tumor cell killing, increased cell-surface GD2 expression, and enhanced antitumor immune responses within the tumor microenvironment, supporting PIK3C3/VPS34 inhibition as a promising therapeutic strategy for high-risk neuroblastoma.
