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 3

mcMEDI therapy induces effective local immune activity within primary tumor and TDLN.

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mcMEDI therapy induces effective local immune activity within primary tu...
(A) Schematic of treatment plan. BALB/c mice (n = 10 per group) were injected with 2 × 105 4T1-Luc mammary carcinoma cells into the fourth mammary fat pad (day 0). Mice were injected peritumorally with 50 μL of mcMEDI and were injected intratumorally with 10 μL of MEDI9197. Both treatment groups were given MEDI9197 at a dose of 0.5 μg per injection at the indicated days. The NT group did not receive MEDI9197. Primary tumors and TDLNs were dissected 14 days after implantation and digested to isolate single cells for the flow cytometry analysis. (B) Primary tumor growth and (C) BW of mice during therapy. (D) Activated (CD69+) and effector (CXCR3+) T cell phenotypes (CD8+ or CD4+) in individual tumors per 105 live cells are shown. (E) Ex vivo images of dissected TDLNs and (F) their size. Scale bar: 5 mm. (G) Activated (CD69+) T cells, activated (MHCII+, CD86+) DCs in individual TDLNs are shown. (H and I) 4T1 tumor-bearing BALB/c mice (n = 5–6 per group) were injected with 0.5 μg of mcMEDI (PT) or MEDI9197 (IT) once at day 7. Dissected tumors and TDLNs at 12 hours after injection were digested into single cells, stained, and assessed by flow cytometry. H shows the frequency of activated dendritic cells (CD86+) or T cells (CD69+) in tumor tissue, and I shows the frequency of activated resident DCs (CD86+) and T cells (CD69+) in TDLNs. Data are representative of 3 independent experiments for A–G and 2 independent experiments for H and I. 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 F–I.