Rejuvenation of Tumor-Specific T Cells via Ultrahigh DAR Antibody-Polymeric Imidazoquinoline Complexes: Coordinated Targeting of PDL1 and Efficient TLR7/8 Activation in Intratumoral Dendritic Cells.

Abstract

Intratumoral dendritic cells (DCs) are pivotal in tumor treatment due to their immature and pro-tumoral state induced by the tumor microenvironment. Clinically, these immature DCs correlate with disease progression and recurrence, adversely affecting prognosis. Activation of DCs by the TLR7/8 agonist imidazoquinoline (IMDQ) has yielded promising results, but they are limited by systemic inflammation risks, and high programmed death ligand 1 (PDL1) expression on DCs impedes CD8⁺ T cell activity. Thus, the study introduces an antibody-polymeric IMDQ complex (αPDL1-PLG-IMDQ) with an ultrahigh drug-to-antibody ratio, where αPDL1 is conjugated to Fc-binding peptides on polymeric IMDQ. This complex targets high PDL1-expressing intratumoral DCs with high probability, inducing PDL1-mediated endocytosis to deliver IMDQ to TLR7/8 within endosomes, effectively activating DCs (CD11c⁺MHC II⁺: 2.33% versus 1.09%, CD11c⁺CD86⁺: 2.49% versus 1.00% on tumors compared to phosphate-buffered saline treatment) and priming T cells. It also blocks PDL1/PD1 interactions, enhancing tumor-specific T-cell activation and memory. Notably, αPDL1-PLG-IMDQ achieved a 97% tumor inhibition rate, prevented tumor regrowth in rechallenge experiments, and reduced lung metastases of tumors by 83%. These findings underscore its potential for intratumoral DC-targeted immunotherapy and novel systemic IMDQ and checkpoint inhibitor combinations.