TY - JOUR
T1 - Targeting antigen-presenting cells by anti-PD-1 nanoparticles augments antitumor immunity
AU - Ordikhani, Farideh
AU - Uehara, Mayuko
AU - Kasinath, Vivek
AU - Dai, Li
AU - Eskandari, Siawosh K
AU - Bahmani, Baharak
AU - Yonar, Merve
AU - Azzi, Jamil R
AU - Haik, Yousef
AU - Sage, Peter T
AU - Murphy, George F
AU - Annabi, Nasim
AU - Schatton, Tobias
AU - Guleria, Indira
AU - Abdi, Reza
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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.
KW - Animals
KW - Antineoplastic Agents, Immunological/administration & dosage
KW - Cell Line, Tumor/transplantation
KW - Cytokines/immunology
KW - Dendritic Cells/drug effects
KW - Disease Models, Animal
KW - Dose-Response Relationship, Drug
KW - Drug Carriers/chemistry
KW - Female
KW - Humans
KW - Lymphotoxin-alpha/genetics
KW - Mice
KW - Mice, Knockout
KW - Nanoparticles/chemistry
KW - Neoplasms/drug therapy
KW - Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors
KW - Spleen/cytology
KW - Treatment Outcome
U2 - 10.1172/jci.insight.122700
DO - 10.1172/jci.insight.122700
M3 - Article
C2 - 30333312
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - e122700
ER -