PLGA micro/nanoparticle vaccination elicits non-tumor antigen specific resident memory CD8⁺ T cell protection from hepatocellular carcinoma

Together, tumor and virus-specific tissue-resident CD8⁺ memory T cells (TRMs) of hepatocellular carcinoma (HCC) patients with Hepatitis B virus (HBV) infection can provide rapid frontline immune surveillance. The quantity and activity of CD8⁺ TRMs were correlated with the relapse-free survival of patients with improved health. However, HBV-specific CD8⁺ TRMs have a more exhausted phenotype and respond more actively under anti-PDL1 or PD1 treatment of HBV⁺HCC patients. Vaccination strategies that induce a strong and sustained CD8⁺ TRMs response are quite promising. Herein, a biodegradable poly(D,L-lactide-co-glycolide) microsphere and nanosphere particle (PLGA N.M.P) delivery system co-assembled by anti-PD1 antibodies (aPD1) and loaded with ovalbumin (OVA-aPD1 N.M.P) was fabricated and characterized for size (200 nm and 1 μm diameter), charge (-15 mV), and loading efficiencies of OVA (238 μg mg^-1 particles) and aPD1 (40 μg mg^-1 particles). OVA-aPD1 N.M.P could stimulate the maturation of BMDCs and enhance the antigen uptake and presentation by 2-fold compared to free OVA. The nanoparticles also induced the activation of macrophages (RAW 264.7) to produce a high level of cytokines, including TNF-α, IL-6 and IL-10. In vivo stimulation of mice using OVA-aPD1 N.M.P robustly enhanced IFN-γ-producing-CD8⁺ T cell infiltration in tumor tissues and the secretion of IgG and IgG2a/IgG1 antibodies. OVA-aPD1 N.M.P delivered OVA to increase the activation and proliferation of OVA-specific CD8⁺ TRMs, and its combination with anti-PD1 antibodies promoted complete tumor rejection by the reversal of tumor-infiltrating CD8⁺ T cell exhaustion. Thus, PLGA N.M.P could induce a strong CD8⁺ TRMs response, further highlighting its therapeutic potential in enhancing an antitumor immune response.