定义纳米级人工抗原呈递细胞上肽-MHC 的关键价态以在体内扩增内源性肿瘤特异性 T 细胞

Expanding tumor antigen-specific T-cells in vivo remains a major challenge in developing effective cancer immunotherapeutics. Artificial antigen-presenting cells (aAPCs) have the potential to overcome this challenge, but formulating aAPCs without correlating the in vivo dynamics of T-cell expansion often leads to suboptimal T-cell responses.

Here, we have defined the critical effect of the peptide-major histocompatibility complex (p-MHC) valency displayed along with co-stimulatory molecules on iron-oxide nanoparticle-based aAPCs in vivo and demonstrated that the functionality of these aAPCs is governed by the p-MHC valency. Nanoscale aAPCs engage cognate CD8+ T-cells directly to induce the formation of T-cell receptor (TCR) microclusters, leading to nuclear translocation of nuclear factor of activated T-cells (NFAT) in a p-MHC valency-dependent manner.

Nanoscale aAPCs, presenting p-MHCs above the threshold valencies, promoted the expansion and tumor infiltration of adoptively transferred and endogenous tumor-specific CD8+ T-cells in tumor situations. The treatment effectively inhibited tumor growth, highlighting the importance of defining the threshold valency of p-MHC in developing aAPCs for effective immunotherapies.