Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
Aurélien Marabelle, … , Victor Tse, Ronald Levy
Aurélien Marabelle, … , Victor Tse, Ronald Levy
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2447-2463. https://doi.org/10.1172/JCI64859.
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Research Article

Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

Abstract

Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.

Authors

Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy

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Figure 9

CNS lymphoma development after i.c. tumor challenge.

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CNS lymphoma development after i.c. tumor challenge. (A) CNS disease-fre...
(A) CNS disease-free survival after i.c. challenge. CNS protection of mice previously cured from s.c. lymphoma with i.t. CpG plus low-dose αOX40/CTLA4. 150 days later, these mice and naive mice were challenged i.c. with 0.5 × 106 A20 tumor cells. Mice were sacrificed when presenting with neurological symptoms. *P < 0.05. (B) CNS disease-free survival in the same experimental settings but with mice depleted of CD4+ or CD8+ T cells a few days prior the i.c. challenge. (C) CNS lymphoma mouse model. 0.5 × 106 to 1 × 106 A20 or A20-Luc lymphoma tumor cells were stereotactically injected into the brain parenchyma of syngeneic BALB/c mice. Tumor development was monitored longitudinally using bioluminescence signal of A20-Luc tumor cells. i.c. tumor engraftment rate was higher than 95%. The bioluminescence signal after A20-Luc injections revealed spontaneous leptomeningeal metastases in 20% to 40% of the cases. The correlation between brain and spinal cord bioluminescent signals and pathological infiltration by tumor cells was confirmed by histology (Supplemental Figures 2 and 3). White arrows indicate the localization of the small blue tumor cells within the brain or the spinal cord after H&E staining. (D) CNS lymphoma treatment groups. Mice were challenged s.c. with 10 × 106 A20 and i.c. with 1 × 106 A20-Luc tumors cells. Once the tumors were established (day 5 after i.c. tumor inoculation), these mice received either systemic conventional therapies (chemotherapies or passive immunotherapy) or local in situ active immunomodulation.