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Coimmunomodulation of tumor and tumor-draining lymph nodes during in situ vaccination promotes antitumor immunity
Moonkyoung Jeong, … , Dong-Hyun Kim, Ji-Ho Park
Moonkyoung Jeong, … , Dong-Hyun Kim, Ji-Ho Park
Published May 17, 2022
Citation Information: JCI Insight. 2022;7(12):e146608. https://doi.org/10.1172/jci.insight.146608.
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Research Article Therapeutics Vaccines

Coimmunomodulation of tumor and tumor-draining lymph nodes during in situ vaccination promotes antitumor immunity

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Abstract

In situ vaccination has demonstrated the feasibility of priming local immunity for systemic antitumor responses. Although direct intratumoral (IT) delivery of adjuvant is the mainstay, tumor-draining lymph nodes (TDLNs) also play essential roles in antitumor immunity. We report that directing an adjuvant to both tumors and TDLNs during in situ vaccination can induce robust antitumor responses. Conventional IT dosing leads to tumor-limited delivery of agents; however, delivery to both tumors and TDLNs can be ensured through a micellar formation. The peritumoral delivery of micellar MEDI9197 (mcMEDI), a toll-like receptor 7/8 agonist, induced significantly stronger innate and adaptive immune responses than those on conventional dosing. Optimal dosing was crucial because excessive or insufficient accumulation of the adjuvant in the TDLNs compromised therapeutic efficacy. The combination of local mcMEDI therapy significantly improved the efficacy of systemic anti–programmed death receptor 1 therapy. These data suggest that rerouting adjuvants to tumors and TDLNs can augment the therapeutic efficacy of in situ vaccination.

Authors

Moonkyoung Jeong, Heegon Kim, Junyong Yoon, Dong-Hyun Kim, Ji-Ho Park

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Figure 1

Local administration of micelles facilitates primary tumor and TDLN delivery.

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Local administration of micelles facilitates primary tumor and TDLN deli...
BALB/c mice were injected with 2×105 4T1-Luc mammary carcinoma cells into the fourth mammary fat pad. When the tumor size reached approximately 50 mm3, micelles incorporating DiR were administered locally. (A) Schematic of local administration. Peritumoral administration was performed by injecting 50 μL of solutions into the peritumoral region approximately 5 mm away from the tumor. IT administration was performed by injecting 10 μL of solutions directly into the center of the tumor. (B and C) Ex vivo fluorescence images of tumor and TDLNs at 96 hours after peritumoral or IT micelle dosing and their quantification (n = 5). (D and E) Either conventional IT dosing of DiR or peritumoral dosing of micelle incorporating DiR was performed in 4T1-Luc tumor-bearing mice. For conventional IT dosing, DiR was first dissolved in Tween 80 (40 mg/mL) and then ethanol (2.5 mg/mL) sequentially, which was diluted with PBS into a final concentration. IT administration was performed by injecting 10 μL of solutions directly into the center of the tumor. Ex vivo fluorescence images of tumor and TDLNs at 96 hours after micelle or conventional IT dosing shown in D and their quantification in E (n = 3). Scale bars: 5 mm. Unpaired 2-tailed Student’s t test. Data are representative of 2 independent experiments. Data presented as mean ± SEM. LN, lymph node; In, inguinal; Ax, axillary; CL, contralateral; %ID/g, percent of injected dose per gram tissue.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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