CCR9+ T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9+ cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity–responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9+CD8+ T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell–dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein–1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9+CD8+ T cell tumor infiltration.

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Immunotherapy has been successfully used in the treatment of multiple malignancies, but clinical studies revealed low response rates. Thus, the development of new effective immunotherapeutic modalities is urgently needed. Successfully inducing tumor cell death with enhanced antigenicity is important for the expansion and differentiation of tumor-specific CD8 + cytotoxic T lymphocytes. Cationic liposome/DNA complexes (CLN/DNA), which usually have obvious cytotoxic effects, may improve the antitumor immunity through enhancing the immunogenicity of dying tumor cells. Herein, we report that a plasmid DNA-encapsulated cationic lipid nanoparticle formulated with cholesterol, DOTAP, and DSPE-mPEG 2000 significantly increases the tumor cell death with high antigenicity in vitro. Furthermore, the cationic liposome/DNA complex (CLN/DNA) treatment promotes the activation of dendritic cells (DCs). We also find that the intratumorally injected CLN/DNA successfully promoted the activation of DCs in the tumor-draining lymph node. Importantly, both local tumor growth and distant tumor formation were significantly inhibited by T cell-dependent antitumor immune responses after intratumoral injection of CLN/DNA. This study presents a simple and effective strategy for improving the cancer immunotherapy.

This study provides new avenues for cascade amplification of the antitumor effects by regulating the tumor microenvironment.

Gold nanoparticles (AuNPs) have been extensively explored as a drug carrier and have been widely used to provide advanced biomedical research tools in diagnostic imaging and therapy for cancer. Although the mononuclear phagocyte system and immune system are known to play the main roles in the clearance of AuNPs during the circulation, the particle distribution within the immune cells under the condition of immune dysfunction caused by tumor growth has not been thoroughly studied. Here, the cellular distribution of Cy5 labeled AuNPs with diameters of 5, 30 and 50 nm is characterized within the immune populations of the blood, spleen and bone marrow from tumor free and tumor bearing mice using flow cytometry. Tumor-associated immune dysfunction was observed in all immune organs and cell lineages, and it changed with tumor growth. Furthermore, the particle cellular distribution significantly changed in the tumor bearing mice compared with the tumor free mice. Finally, the particle distribution in the immune cells was also different at different stages of the tumor. Overall, these results can help inform and influence future AuNP design criteria including the future applications for nanoparticle-mediated cancer therapy.

CD40 is an important costimulatory molecule expressed on antigen-presenting cells (APCs) and plays a critical role for APC activation, offering a promising therapeutic target for preventing allograft rejection. Here, we developed a biodegradable nanoparticle small interfering RNA delivery system (si CD40 /NPs) to effectively deliver CD40 siRNA (si CD40 ) into hematopoietic stem cells (HSCs), myeloid progenitors, and mature dendritic cells (DCs) and macrophages. Injection of si CD40 /NPs not only down-regulated CD40 expression in DCs and macrophages but also inhibited the differentiation of HSCs and/or myeloid progenitors into functional DCs and macrophages. Furthermore, si CD40 /NPs treatment significantly prolonged allograft survival in mouse models of skin allotransplantation. In addition to reiteration of the role of CD40 in APC activation, our findings highlight a previously unappreciated role of CD40 in DC and macrophage differentiation from their progenitors. Furthermore, our results support the effectiveness of si CD40 /NPs in suppressing alloimmune responses, providing a potential means of facilitating tolerance induction and preventing allotransplant rejection.

Modification with polyethylene glycol (PEG), or PEGylation, has become a popular method to improve the efficiency of drug delivery in vivo using nanoparticle-based delivery systems. The PEG end-group plays an...