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 3

Local immunomodulation does better than systemic immunomodulation for the efficacy of antitumor immune responses.

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Local immunomodulation does better than systemic immunomodulation for th...
(A) Mice were challenged s.c. with 5 × 106 A20 tumor cells on the right and left flanks. Therapy was started when tumors reached 0.5–0.7 cm in diameter (usually between day 5 and 8). Treated mice received CpG i.t. only in their right tumor for 5 consecutive days. On day 1 and 5 of CpG therapy, αOX40 and αCTLA4 mAbs were either injected i.p. or i.t. (together with CpG in the right tumor). The systemic antitumor immune response generated by these systemic (i.p.) and local (i.t.) maneuvers was assessed by measuring the size of the contralateral (noninjected) left tumor and mouse disease-free survival. Results were pooled from 2 distinct experiments (n = 10 mice per group). (B) Tumor growth of the distant tumors (nontreated left tumors) when mAbs were injected systemically (i.p.) or locally (i.t. into the right tumor). Black arrows indicate day 1 of therapy. Both strategies (mAbs injected i.p. or i.t.) result in disappearance of the distant (left) tumors. (C) Relapse-free survival of mice treated with either local or systemic immunomodulation. Most of the mice treated systemically (i.p.) with αOX40/CTLA4 relapsed in the left tumor-draining lymph nodes, whereas almost all the mice who received αOX40 and αCTLA4 locally (i.t.) had a long-term survival (*P = 0.002). The number of mice per group is shown into parenthesis. (D) Therapeutic efficacy of 1:100 and 1:1,000 doses of αOX40 and αCTLA4 either injected i.p. or i.t. together with CpG and the resulting long-term disease-free survival. ttt, treatment.