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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 6

T cell profile of the spleens from anti–PD-1 NP–treated B16-F10 melanoma tumor–bearing C57BL/6 mice at day 17 following tumor cell inoculation.

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T cell profile of the spleens from anti–PD-1 NP–treated B16-F10 melanoma...
(A and B) The spleens of mice in the anti–PD-1 NP–treated group had higher percentages of CD4+ and CD8+ effector memory T cells, CD4+CD69+ T cells, and CD8+CD69+ T cells in comparison with anti–PD-1– or vehicle-treated mice. (C) The percentage of CD4+IFN-γ+ T cells was significantly higher in the spleens of mice treated with anti–PD-1 NPs than in those of mice receiving free anti–PD-1 (anti–PD-1) or vehicle. (D) A significantly higher percentage of CD11c+CD86+ cells was observed in the spleens of mice treated with anti–PD-1 NPs in comparison with those of mice treated with free anti–PD-1 or vehicle. Data are presented as mean ± SEM (n = 3 mice/group). *P<0.05; **P<0.01, calculated by 1-way ANOVA.

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ISSN 2379-3708

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