Poor infiltration of activated lymphocytes into tumors can be a fundamental factor limiting their efficacy and impeding the therapeutic effect of the checkpoint blockade immunotherapy. A tumor-penetrating peptide, iRGD, has a well-defined role in delivering drugs into extravascular tumor tissues in both the combination regimen and conjugated pattern, Here, we explored for the first time whether this cycled peptide could facilitate the infiltration of lymphocytes into tumor and furtherly overcome resistance to PD1 gene knockout immunotherapy.
We used polyethylene glycol-conjugated phospholipid (PEG-lipid) derivatives, a time-efficient and versatile platform, to immobilize iRGD on T cell membrane. The ability of iRGD modified or co-applied lymphocytes infiltration was detected in both the 3D tumor spheroids in vitro and subcutaneous tumor model and peritoneal tumor model of gastric cancer in vivo. Furthermore, the synergistic effect of iRGD modification and PD-1 gene knockout in adoptive T cell transfer immunotherapy was examined in a xenograft model of EBV-associated gastric cancer.
In this study, we showed that T cells could be modified by the synthetic iRGD-PEG-lipid without compromising their vitality, expansion, phenotype and effector function. In vitro, co-administration of iRGD could promote the infiltration of T cells while iRGD modification made T cells spread more extensively throughout the multicellular spheroids. Near infrared results showed that iRGD modification made a tenfold improvement infiltration of T cells into tumors without a parallel increase in normal tissues. Most importantly, we demonstrated that iRGD modified T cells had superior antitumor efficiency owing to sufficiently increased T cells infiltration, and exhibited robust synergistic effect with PD-1 gene knockout immunotherapy.
Our study indicates that modification of T cell membrane with iRGD might be a potent strategy to increase T cells infiltration, thereby overcome the bottleneck of solid tumor immunotherapy.
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All authors have declared no conflicts of interest.