Coimmunomodulation of tumor and tumor-draining lymph nodes during in situ vaccination promotes antitumor immunity
Moonkyoung Jeong, Heegon Kim, Junyong Yoon, Dong-Hyun Kim, Ji-Ho Park
Moonkyoung Jeong, Heegon Kim, Junyong Yoon, Dong-Hyun Kim, Ji-Ho Park
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Research Article Therapeutics Vaccines

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

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 5

Optimal dose of mcMEDI is required for effective systemic antitumor immunity.

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Optimal dose of mcMEDI is required for effective systemic antitumor immu...
(A) Schematic of treatment plan. BALB/c mice (n = 4–5 per group) were injected with 2 × 105 4T1-Luc mammary carcinoma cells into the fourth mammary fat pad (day 0). Treatment groups were given mcMEDI peritumorally with various doses of 4.5 μg, 1.5 μg, and 0.5 μg per injection at days 5, 7, 9, and 11. The NT group did not receive MEDI9197. Tumors and TDLNs were dissected at day 14. (B) Primary tumor growth and (C) BW of mice during therapy. (D) Ex vivo images of the primary tumor and TDLNs surgically removed from mice. Scale bar: 5 mm. (E and F) Weight of tumor and size of TDLN. (G) Representative flow dot plots showing TDLN cell loss in high dose regimens. (H) Kaplan-Meier survival curves of mice. Median survival days (ms) are listed. The experiment was performed once. Data presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001; 2-way RM ANOVA and Tukey’s multiple comparisons test for B and C, 1-way ANOVA and Tukey’s multiple comparisons test for D and E, log-rank (Mantel-Cox) test for H. n/a, not achieved.