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 4

Combination therapy of i.t. CpG and low-dose immunomodulatory antibodies is specifically required to trigger an efficient antitumor immune response.

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Combination therapy of i.t. CpG and low-dose immunomodulatory antibodies...
Mice were treated as in Figure 3A, and. i.t. injections of therapy were done in right (local) tumors (red), and systemic antitumor effect was assessed by measuring growth of left (distant) tumors (blue). CpG was injected at 100 μg daily for 5 consecutive days. Low doses of mAbs (4 μg αOX40 or rat isotype or/and 1 μg αCTLA4 or hamster isotype) were injected on day 1 and 5 of CpG therapy into the same tumor. (A) Growth of distant tumors without therapy. (B–F) Systemic antitumor effect of CpG injections (B) alone on injected and distant tumors; (C) in combination with rat and hamster isotypes of αOX40 and αCTLA4 mAbs, respectively; (D) in combination with αOX40; (E) in combination with αCTLA4; and (F) in combination with αOX40 and αCTLA4. Previous curves pooled from at least 2 different experiments per group. (A–F) The number of surviving mice at day 60 is shown in parenthesis. (G) Survival of mice bearing 2 s.c. tumors (right and left flanks) that received CpG plus rat/hamster isotypes, CpG plus αOX40, CpG plus αCTLA4, or CpG plus αOX40/CTLA4 in right tumors. Survival with CpG plus αOX40/CTLA4 was significantly higher than with CpG plus αOX40 (P = 0.004) or CpG plus αCTLA4 (P = 0.03). Data are pooled from at least 2 different experiments per group; the number of mice per group is shown into parenthesis (*P < 0.05). Systemic antitumor effect of (H) αOX40 plus αCTLA4 local low-dose therapy without CpG (n = 4) and (I) s.c. CpG and i.t. αOX40 plus αCTLA4. (J) Survival of tumor-bearing mice treated with i.t. CpG and low-dose αOX40 plus αCTLA4 in the context of CD4 or CD8 T cell depletion (*P < 0.05).