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Targeting antigen-presenting cells by anti–PD-1 nanoparticles augments antitumor immunity
Farideh Ordikhani, … , Indira Guleria, Reza Abdi
Farideh Ordikhani, … , Indira Guleria, Reza Abdi
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e122700. https://doi.org/10.1172/jci.insight.122700.
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Research Article Immunology

Targeting antigen-presenting cells by anti–PD-1 nanoparticles augments antitumor immunity

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Abstract

Recent studies in cancer research have focused intensely on the antineoplastic effects of immune checkpoint inhibitors. While the development of these inhibitors has progressed successfully, strategies to further improve their efficacy and reduce their toxicity are still needed. We hypothesized that the delivery of anti–PD-1 antibody encapsulated in PLGA nanoparticles (anti–PD-1 NPs) to the spleen would improve the antitumor effect of this agent. Unexpectedly, we found that mice treated with a high dose of anti–PD-1 NPs exhibited significantly higher mortality compared with those treated with free anti–PD-1 antibody, due to the overactivation of T cells. Administration of anti–PD-1 NPs to splenectomized LT-α–/– mice, which lack both lymph nodes and spleen, resulted in a complete reversal of this increased mortality and revealed the importance of secondary lymphoid tissues in mediating anti–PD-1–associated toxicity. Attenuation of the anti–PD-1 NPs dosage prevented toxicity and significantly improved its antitumor effect in the B16-F10 murine melanoma model. Furthermore, we found that anti–PD-1 NPs undergo internalization by DCs in the spleen, leading to their maturation and the subsequent activation of T cells. Our findings provide important clues that can lead to the development of strategies to enhance the efficacy of immune checkpoint inhibitors.

Authors

Farideh Ordikhani, Mayuko Uehara, Vivek Kasinath, Li Dai, Siawosh K. Eskandari, Baharak Bahmani, Merve Yonar, Jamil R. Azzi, Yousef Haik, Peter T. Sage, George F. Murphy, Nasim Annabi, Tobias Schatton, Indira Guleria, Reza Abdi

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Figure 1

Characterization of anti–PD-1 NPs in vitro.

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Characterization of anti–PD-1 NPs in vitro.
(A) Schematic illustration o...
(A) Schematic illustration of anti–PD-1 loaded in PLGA NPs. (B) Representative TEM image of anti–PD-1 NPs, negatively stained, imaged at 80.0 kV (scale bar: 100 nm) revealing uniform spherical shape of NPs. (C) Size distribution of anti–PD-1 NPs, as measured by DLS, showing the hydrodynamic size of NPs to be 158.3 (±4.2) nm. (D) Release kinetics of anti–PD-1 mAb from PLGA NPs revealing sustained release of anti–PD-1 mAb over time with activity maintained for 2 weeks. Data are mean ± SEM of 3 preparations. (E) Anti–PD-1 NPs enhanced T cell proliferation. After an incubation period of 24 hours (hr), CD11c+ DCs were washed with DPBS, and allogeneic CD3+ T cells were added to these cells. The cells were incubated together for 48 hr at 37°C in a humidified atmosphere containing 5% CO2. The cells were labeled with [3H]-Thymidine (0.25 μCi per well) for an additional 16 hr to measure T cell proliferation. [3H]-Thymidine incorporation results show significant proliferation responses to anti–PD-1 NPs in comparison with control, free anti–PD-1 (anti–PD-1), and empty NPs. CPM, counts per minute. (F–H)Representative images and bar graphs show median fluorescence intensities for (F) CD40, (G) CD80, and (H) CD86 among CD11c+ DCs. Data represent mean ± SEM. **P<0.01; ***P<0.005 calculated by 1-way ANOVA.

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