Adaptive Antitumor Immune Response Stimulated by Bio-nanoparticle Based Vaccine and Checkpoint Blockade

Background: Interactions between tumor and microenvironment determines the response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors. Aspartate beta-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods: : Orthotopic TNBC and subcutaneous HCC murine models were established. Immunohistochemistry, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results: : The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based vaccine targeting ASPH was administrated to BALB/c mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In the control group, autocrine CXCL13-CXCR5 axis promoted cancer development and progression. Inhibition between PD-L1 + cancer cells and PD-1 + T cells resulted in T cell exhaustion and apoptosis. In contrast, combination therapy significantly suppressed primary hepatic or mammary tumor growth with distant pulmonary metastases in TNBC. An adaptive immune response was attributed to expansion of activated CD4 + Th1/CD8 + CTLs with enhanced effector function and high titers of ASPH-specific antibody. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH + cancer cells recruited CXCR5 + /CD8 + T lymphocytes to tertiary lymphoid structures (TLSs), which secreted CXCL13 to recruit more CXCR5 + immune cells and to lyse CXCR5 + cancer cells. Upon combination treatment, the presence of TLSs predicts sensitivity to immune checkpoint inhibitor blockade. Conclusions: : Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH combined with an immune checkpoint inhibitor represents a new approach for TNBC and HCC.