Asynchronous blockade of PD-L1 and CD155 by polymeric nanoparticles inhibits triple-negative breast cancer progression and metastasis

PD-L1/PD-1 blockade therapy shows durable responses to triple-negative breast cancer (TNBC), but the response rate is low. CD155 promotes tumor metastasis intrinsically and modulates the immune response extrinsically as the ligand of DNAM-1 (costimulatory receptor) and TIGIT/CD96 (coinhibitory receptors). Herein, we verified that TNBC cells coexpressed PD-L1 and CD155. By examining the receptors of PD-L1 and CD155 on TNBC tumor-infiltrating lymphocytes (TILs) over time, we observed that PD-1 and DNAM-1 were upregulated early, whereas CD96 and TIGIT were upregulated late in CD8+ TILs. Based on these findings, we developed CD155 siRNA (siCD155)-loaded mPEG-PLGA-PLL (PEAL) nanoparticles (NPs) coated with PD-L1 blocking antibodies (P/PEALsiCD155) to asynchronously block PD-L1 and CD155 in a spatiotemporal manner. P/PEALsiCD155 maximized early-stage CD8+ T cell immune surveillance against 4T1 tumor, whereas reversed inhibition status of the late stage CD8+ T cells to prevent 4T1 tumor immune escape. In addition, the combination of P/PEALsiCD155 and tumor-specific CD8 T cells induced immunogenic cell death (ICD) of 4T1 cells to further boost immune checkpoint therapy. Most importantly, P/PEALsiCD155 displayed excellent TNBC targeting and induced CD8+ TILs-dominant intratumor antitumor immunity to efficiently inhibit TNBC progression and metastasis with excellent safety in a syngeneic 4T1 orthotopic TNBC tumor model.