IMMU-23. ANTIGEN-SPECIFIC EFFECTOR MEMORY CD4+ T CELLS AND CCL3 POTENTIATE DENDRITIC CELL VACCINES AND ANTITUMOR IMMUNITY

Abstract INTRODUCTION Efficacy of dendritic cell (DC) vaccines for glioblastoma (GBM) has been limited by suboptimal migration to draining lymph nodes. Protein antigens induce robust T cell responses that can potentiate innate antigen presenting cells such as DCs. Our previous work in patients with GBM and corroborating mouse models receiving tumor antigen-specific DCs revealed that migration and antitumor responses were significantly enhanced by CD4+ T cell memory responses to a different protein antigen, tetanus-diphtheria (Td) toxoid. Furthermore, vaccine responses were dependent on the chemokine CCL3. Here, we investigated how memory CD4+ T cells interact with cognate antigens Td and the Mycobacterium tuberculosis antigen 85B (Ag85B) to enhance responses to ovalbumin (OVA)-expressing DCs and tumors. METHODS C57BL/6 and CD4 + 85B TCR transgenic mice were used to study the effects of Td and Ag85B-specific responses on OVA-DC migration and efficacy. RESULTS One day following Td and Ag85B preconditioning, there is an influx of CD4+ T cells in the skin site (p=0.002), and this is dependent on the protein antigen recall response (p=0.005). Both Td and 85B preconditioning led to locally induced CCL3 and increased migration of OVA-DCs (Td, p=0.002; Ag85B, p=0.001). Depletion of CD4+ T cells resulted in a loss of induced CCL3 as well as abrogation of increased DC migration (p=0.005). Mice with established B16/F10-OVA tumors receiving Td preconditioning demonstrated suppressed tumor growth compared to controls, which was abrogated in Ccl3-/- hosts. However, adoptive transfer of Td memory CD4+ T cells and exogenous CCL3 rescued the effect of suppressed growth (Day 21 mean tumor volumes, p=0.017). CONCLUSIONS The induction of CD4+ memory responses to protein antigens can sufficiently facilitate the increased migration of tumor antigen-specific DCs and promote antitumor immunity. This axis of the adaptive immune response relies on host CCL3, which can serve as a potent immunotherapy adjuvant in future studies.