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Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy
A Katz1, L M Shulman, A Porgador
1Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
We investigated the antitumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic B16 melanoma clone F10.9. These tumor cells were found to have very low levels of IL-6 receptors and in vitro IL-6 had no effect on cell proliferation or on the expression of MHC class I antigens. However, in vivo IL-6 was active against the metastatic growth of this tumor in mice, presumably through indirect immune effects. Low-dose IL-6 (1-10 micrograms/day), in three daily injections, 4 days a week, for 3 weeks, strongly inhibited the formation of experimental lung metastases following intravenous tumor cell inoculation. IL-6 therapy could be started even 10 days after tumor injection, when metastases are already established. Moreover, IL-6 treatment of mice bearing F10.9 tumors in the footpads resulted in complete protection against pulmonary spontaneous metastasis and in long-term survival. Histology confirmed the absence of micrometastases in most of the IL-6-treated animals. Analysis of the cytolytic activity of splenocytes at different times during therapy of tumor-bearing mice revealed significant lysis (up to 42%) of the melanoma F10.9 cells in the mice receiving IL-6 but not in the control mice.
Insights
Human recombinant interleukin-6 (hrIL-6) effectively inhibited B16 melanoma metastasis in mice, even when treatment began after metastases formed. This suggests indirect immune mechanisms contribute to hrIL-6
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- The B16 melanoma clone F10.9 exhibits high metastatic potential.
- B16 melanoma F10.9 cells show low expression of interleukin-6 (IL-6) receptors.
- In vitro, IL-6 does not affect melanoma cell proliferation or MHC class I expression.
Purpose of the Study:
- To investigate the in vivo antitumor effects of human recombinant IL-6 (hrIL-6) on highly metastatic B16 melanoma F10.9.
- To determine if hrIL-6 can inhibit the formation and growth of experimental and spontaneous metastases.
- To explore the potential immune mechanisms underlying hrIL-6's anti-metastatic activity.
Main Methods:
- Administration of low-dose hrIL-6 (1-10 micrograms/day) via daily injections, 4 days/week for 3 weeks.
- Intravenous inoculation of B16 melanoma F10.9 cells to establish experimental lung metastases.
- Treatment of mice with established footpad tumors to assess spontaneous pulmonary metastasis.
- Analysis of splenocyte cytolytic activity against melanoma F10.9 cells.
Main Results:
- hrIL-6 strongly inhibited experimental lung metastasis formation following intravenous tumor cell inoculation.
- IL-6 therapy demonstrated efficacy even when initiated 10 days after tumor injection, targeting established metastases.
- Treatment of mice with footpad tumors led to complete protection against spontaneous pulmonary metastasis and long-term survival.
- Histological analysis confirmed the absence of micrometastases in most hrIL-6-treated animals.
- Splenocytes from hrIL-6-treated mice exhibited significant in vitro cytolytic activity against B16 melanoma F10.9 cells (up to 42%).
Conclusions:
- In vivo, hrIL-6 exhibits potent anti-metastatic effects against B16 melanoma F10.9, likely mediated by indirect immune responses.
- IL-6 therapy can overcome established metastases and prevent spontaneous spread, offering a potential therapeutic strategy.
- The observed enhancement of splenocyte-mediated tumor cell lysis suggests a role for adaptive immunity in hrIL-6's efficacy.
