Medical Student Duke University School of Medicine Durham, North Carolina, United States
Disclosure(s):
Sirajbir Sodhi, BS: No financial relationships to disclose
Introduction/Rationale: The role of B cells and antibodies in cancer immunity remains unresolved, with studies reporting both protective and deleterious effects across tumor types. A mechanistic explanation for this variability has been lacking. We hypothesized that neoantigen membrane localization governs whether endogenous antibodies drive tumor control.
Methods: We analyzed The Cancer Genome Atlas (TCGA) data to assess the prognostic significance of intratumoral IgG. Syngeneic tumors were engineered to express membrane-localized or cytoplasmic neoantigens, then evaluated for growth, antibody class switching, and immune composition. CXCL13 and IL-21-expressing cells were used to enhance IgG responses. Adenoviral vaccines encoding wild-type Trop2 or the T256R variant were employed to test how antigen localization influences vaccines.
Results: TCGA analyses showed that the prognostic significance of IgG varies markedly across cancer types. In vivo, we found that membrane-localized nantigens, unlike cytoplasmic antigens, stimulated robust class-switched IgG production, enhanced myeloid cell activation, and limited tumor growth, independent of CD8 T cells. Alteration of antigen location to the membrane was sufficient to convert colorectal cancer models (where IgG predicts poor outcomes) into settings in which antibodies contributed to tumor control. These effects required CD4 T cell help and intact Fc receptor signaling. Consistent with this effect, expression of CXCL13 and IL-21 amplified antibody-mediated tumor control, with the combination providing the greatest benefit. Finally, the Trop2 T256R neoantigen, which disrupts membrane trafficking and reduces antibody accessibility, led to markedly diminished vaccine-induced tumor control, despite generating comparable T cell responses to wild-type Trop2.
Conclusion: This work defines antigen membrane localization as a key determinant of productive humoral anti-tumor immunity, providing a mechanistic basis for incorporating humoral immunity into cancer immunotherapy.
