Endogenous neoantigen specific antibodies mediate anti-tumor responses and determine vaccine efficacy 2308188

Abstract Introduction 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. Funding Source This work was supported by the National Institutes of Health (NIH) (R01CA238217-01A1/02S1 to ZCH), the Department of Defense (DOD) (W81XWH-20-1-0346 to ZCH and W81XWH-21-2-0031 to HKL/ZCH), and institutional support from the Office of Physician Scientist Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)