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.
View: Text | PDF | Erratum
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

×

Figure 11

i.t. low-dose immunomodulation conveys a sustainable cytotoxic antitumor immune response, even in an immune sanctuary site.

Options: View larger image (or click on image) Download as PowerPoint
i.t. low-dose immunomodulation conveys a sustainable cytotoxic antitumor...
(A) Mice were challenged with 1 × 106 A20 tumor cells i.c. and 10 × 106 A20 tumor cells s.c. and treated with CpG plus low-dose aOX40/CTLA4 as previously described (see Figure 9D). On day 6 after the beginning of therapy, brains were collected and digested, and mononuclear cells were separated by Percoll. These cell suspensions were analyzed by FACS for T cell (CD3+) infiltration (gate on all viable cells, *P < 0.05). (B) Brains of mice bearing CNS lymphoma were extracted on day 7 of therapy and stained by IF for CD8+ and CD4+ T cells (red). Tumor cells were identified by tumor idiotype staining (green). Original magnification, ×20. (C) Ratio of number of brain-infiltrating CD8+ T cells over CD4+ T cells upon therapy. *P < 0.05. (D) Proportion of activated (CD69+) CD8+ T cells upon therapy. *P < 0.05. (E) Brains from CNS lymphoma-bearing mice were collected on day 8 of s.c. therapy and reexposed overnight to irradiated A20 tumor cells. T cells were subsequently stained for surface CD44 and intracellular IFN-γ. (F) As in E, but median values from 5 mice (*P < 0.0001 for both CD8+ and CD4+ cells). (G) Mice cured from CNS lymphoma were rechallenged i.c. 140 days later in the contralateral hemisphere with 0.5 × 106 A20 lymphoma tumor cells as were naive mice. Survival after rechallenge of i.c. cured is shown (6 mice per group, P < 0.001).