Loss of Tumorigenicity and Increased Immunogenicity Induced by Interleukin-10 Gene Transfer in B16 Melanoma Cells

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Abstract
Because interleukin-10 (IL-10) has potent immunosuppressive and anti-inflammatory properties and is produced by some cancers, we hypothesized that its production might play a role in carcinogenesis by inhibiting adequate antitumoral immune responses. To test this hypothesis, retroviral vectors containing the IL-10 cDNA were generated and used to infect B16F1 melanoma cells that were injected subcutaneously in syngeneic mice. Surprisingly, IL-10 gene transfer resulted in a loss of tumorigenicity that was proportional to the amount of IL-10 secreted. Histological analysis showed massive area of necrosis of these tumor cells, with infiltration of polymorphic inflammatory cells. Parental cells simultaneously implanted had decreased tumorigenicity only when mixed with IL10-producing cells, but not when injected contralaterally, suggesting that their eradication is mediated mostly by a local phenomenon. Host T lymphocytes and natural killer (NK) cells were involved in this eradication because IL-10-producing cells grew in nude mice and in CD8+ or NK-depleted mice. Finally, mice injected with IL-10-secreting cells developed an antitumoral systemic immune response able to protect them against a subsequent challenge with parental cells. These results demonstrate that, in some settings, IL10 may have in vivo immunostimulating and proinflammatory properties that need to be considered in its therapeutic development. Interleukin-10 (IL-10) has emerged as a potent immunosuppressive and anti-inflammatory cytokine that mainly inhibits the capacity of antigen-presenting cells to provide stimulatory signals to CD4+ lymphocytes. Because of these properties, several groups are testing the relevance of IL-10 administration or of IL-10 gene transfer for the treatment and/or the prevention of clinical conditions involving either macrophage or T cell activation. Testing the hypothesis that IL-10 production in tumors suppresses antitumoral immune responses, we found, surprisingly, that IL-10 gene transfer in B16F1 melanoma cells induces their loss of tumorigenicity and an immune response able to protect syngeneic animals against a challenge with parental tumor cells. Our experiments demonstrate that, at least in some settings, IL-10 gene transfer has immunostimulating and proinflammatory properties.