Scientist D National Center for Cell Science Brighton, Maharashtra, India
Introduction/Rationale: B cells are increasingly recognized as regulators of tumor immunity, influencing T cell responses and tertiary lymphoid structure formation within the tumor microenvironment (TME). However, the molecular determinants that govern pro- versus anti-tumorigenic B cell states remain poorly defined. We investigated the role of the glycosphingolipid globotriaosylceramide (Gb3), enriched in activated lymphocytes, in shaping B cell–mediated tumor immunity.
Methods: Gb3 levels were genetically modulated using α-galactosidase A–deficient (Gla KO; Gb3 accumulation) and A4galt KO (Gb3-deficient) mice. Tumor growth and immune infiltration were assessed following tumor challenge. B cell–intrinsic effects were evaluated by adoptive transfer of Gb3-high or Gb3-deficient B cells into B cell–deficient (μMT) hosts. Antigen-presenting capacity and CD4⁺ T cell repertoire diversity were analyzed. Therapeutic potential was tested using lipid nanoparticles co-formulated with Gb3 and ovalbumin (OVA) in the B16F10-OVA melanoma model.
Results: Gla KO mice exhibited reduced tumor burden with increased infiltration of B cells, CD4⁺ T cells, and CD8⁺ T cells in the TME, whereas A4galt KO mice showed impaired T cell recruitment and accelerated tumor progression. Adoptive transfer experiments demonstrated a B cell–intrinsic role for Gb3: Gb3-high B cells restricted tumor growth, while Gb3-deficient B cells promoted tumor progression. Mechanistically, Gb3-enriched B cells displayed enhanced antigen presentation and promoted diversification of the CD4⁺ T cell repertoire. Gb3–OVA lipid nanoparticles significantly reduced tumor burden in poorly immunogenic melanoma.
Conclusion: Gb3 acts as a critical regulator of B cell activation and function in tumors, defining a previously unrecognized lipid-mediated axis for enhancing B cell–driven anti-tumor immunity.
