Desmoplastic tumors and their metastases are usually resistant to immunotherapy due to the existence of a suppressive microenvironment in the tumor. We have developed nanoparticles (NPs), i.e. LPD and LCP, for delivering plasmid DNA (pDNA) to the tumor or hepatocytes, respectively. We have also engineered fusion proteins, called traps, that will bind with target cytokines or receptors with high affinity and specificity. Colorectal cancer tends to metastasize to the liver. We hypothesize that CXCL12 generated by the activated hepatic stellate cells attracts tumor cells to the liver. Expression of CXCL12 trap in the liver should neutralize the chemokine and block metastasis. Indeed, delivery of CXCL12 trap pDNA by liver specific LCP NPs transiently inhibited CXCL12 level, reduced both MDSCs and Tregs and enhanced CD8+ T-cells in the liver. Liver metastasis of CT-26 colorectal cancer model could be significantly inhibited. In the KPC orthotopic pancreatic cancer model, co-delivery of both CXCL12 and PD-L1 traps by tumor specific LPD NPs were required to shrink the tumor and inhibit metastasis. In both models, pre-injection of anti-CD8 monoclonal antibody to abrogate the CD8+ T-cells completely blocked the therapy effect, indicating that the trap therapy was mediated by the host immune system.

Nanoparticle mediated remodeling of the suppressive immune microenvironment in tumors

253rd National Meeting (2017)

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