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 tumorinfiltrating 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+ TILsdominant intratumor antitumor immunity to efficiently inhibit TNBC progression and metastasis with excellent safety in a syngeneic 4T1 orthotopic TNBC tumor model.

Automated summary

PD-L1/PD-1 blockade therapy offers durable responses to triple-negative breast cancer (TNBC) with a low response rate. The coexpression of PD-L1 and CD155 on TNBC cells was verified and the use of P/PEALsiCD155 nanoparticles showed promising results in enhancing immune surveillance and preventing immune escape of TNBC tumors. This combination therapy also induced immunogenic cell death (ICD) and effectively inhibited TNBC progression and metastasis with superior safety in a preclinical model.