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Cellular mechanisms of the antitumor activity of recombinant IL-6 in mice
J J Mulé1, M C Custer, W D Travis
1Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Abstract:
The systemic administration of human rIL-6 to mice resulted in the regression of established, 3-day pulmonary micrometastases from two weakly immunogenic tumors, but not from a nonimmunogenic tumor, in the absence of observable toxicity. Although IL-6 alone failed to have a significant therapeutic impact on advanced, 10-day pulmonary macrometastases from weakly immunogenic tumors, substantial cure rates of mice could be achieved when this cytokine was combined with cyclophosphamide. Histologic analysis of the lungs of mice receiving IL-6 revealed infiltration with lymphoid cells during the regression of pulmonary nodules from a weakly immunogenic tumor. IL-6-mediated tumor regression could be abrogated after selective in vivo depletion of either CD4 or CD8 T cell subsets by the systemic administration of specific mAb. In vivo generation of tumor-specific CTL, but not of lymphokine-activated killer cells, was detected in the lungs of IL-6-treated mice during regression of pulmonary metastases. Collectively, these findings demonstrate a role for IL-6 in the treatment of established solid tumors that have the capacity to elicit T cell responses in the host. Differences in host cellular mechanisms involved in tumor regression mediated by immunotherapy using IL-6 vs IL-2 are discussed.
Insights
Interleukin-6 (IL-6) therapy promotes the regression of early-stage lung tumors in mice by activating T cells. Combining IL-6 with chemotherapy enhances cure rates for advanced tumors, highlighting IL-6
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Interleukin-6 (IL-6) is a pleiotropic cytokine with known roles in inflammation and immunity.
- The therapeutic potential of IL-6 in cancer treatment, particularly for established solid tumors, remains incompletely understood.
Purpose of the Study:
- To investigate the efficacy of systemic interleukin-6 (IL-6) administration in treating established pulmonary metastases.
- To elucidate the cellular mechanisms underlying IL-6-mediated tumor regression and its potential synergy with chemotherapy.
Main Methods:
- Systemic administration of human recombinant IL-6 (rIL-6) to mice bearing pulmonary micrometastases and macrometastases from tumors with varying immunogenicities.
- Combination therapy using IL-6 and cyclophosphamide.
- Histological analysis of lung tissue to assess immune cell infiltration.
- In vivo depletion of CD4+ and CD8+ T cell subsets using monoclonal antibodies (mAbs).
- Detection of tumor-specific cytotoxic T lymphocytes (CTL) and lymphokine-activated killer (LAK) cells in the lungs.
Main Results:
- Systemic rIL-6 induced regression of established micrometastases from weakly immunogenic tumors, but not nonimmunogenic tumors, without observable toxicity.
- IL-6 alone had limited impact on advanced macrometastases, but combination with cyclophosphamide achieved substantial cure rates.
- Histological examination revealed lymphoid cell infiltration in regressing tumors.
- IL-6-mediated regression was abrogated by depletion of CD4+ or CD8+ T cells.
- Tumor-specific CTL generation was detected in IL-6-treated mice during metastasis regression.
Conclusions:
- IL-6 plays a significant role in treating established solid tumors capable of eliciting T cell responses.
- IL-6 immunotherapy, particularly in combination with chemotherapy, offers a promising strategy for cancer treatment.
- The mechanism of IL-6-mediated tumor regression involves T cell-dependent cellular immunity, distinct from IL-2 mediated effects.