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Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy
Marieke F. Fransen, … , Thorbald van Hall, Ferry Ossendorp
Marieke F. Fransen, … , Thorbald van Hall, Ferry Ossendorp
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e124507. https://doi.org/10.1172/jci.insight.124507.
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Research Article Immunology Oncology

Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy

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Abstract

PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.

Authors

Marieke F. Fransen, Mark Schoonderwoerd, Philipp Knopf, Marcel G.M. Camps, Lukas J.A.C. Hawinkels, Manfred Kneilling, Thorbald van Hall, Ferry Ossendorp

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Figure 1

Immune activation takes place in tumor-draining, but not in nondraining, lymph nodes.

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Immune activation takes place in tumor-draining, but not in nondraining,...
(A) TDLNs (inguinal and axillary) and NDLNs (opposite flank) were isolated when subcutaneous MC38 tumors reached an average size of 100 mm3 and were analyzed with flow cytometry. Mean fluorescence expression of PD-L1 on myeloid cells (CD19–CD11b+) is shown. Statistical difference was calculated with a paired 2-tailed t test. (B and C) Three days after PD-1 Ab treatment, lymph nodes were analyzed for (B) immune cell counts and numbers of (C, left) CD8+ T cells, (C, middle) proliferating CD8+ T cells, and (C, right) T-bet+ CD8+ T cells. Statistical differences were analyzed with 2-way ANOVA. All data represent mean ± SEM from 1 experiment (n = 4 per group) out of 3 independent experiments with similar outcome (*P < 0.05, **P < 0.01).

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