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Relative contribution of antiproliferative and host immunity-associated activity of mouse interferon in murine tumor
Abstract:
Administration of mouse interferon (IFN; 0.5 to 1 X 10(7) reference units/mg protein) inhibited the growth of Meth A and Meth 1 fibrosarcomas, but to a lesser extent, if at all, the growth of Colon 26 adenocarcinoma in BALB/c mice. The in vitro IFN sensitivity of these three tumors was not consistent with the in vivo therapeutic response in mice bearing these tumors under the present experimental conditions; Colon 26, the most sensitive of the three tumors in the in vitro antiproliferation test, did not respond or responded most poorly to IFN therapy; furthermore, Meth A and Meth 1 tumors responded similarly well to IFN therapy, although there was about a 100-fold difference in their in vitro IFN sensitivity. These results as well as the kinetic analysis of IFN concentrations of the serum of Meth A- or Colon 26-bearing mice did not indicate that the antiproliferative activity of IFN was solely responsible for its in vivo therapeutic effect. In contrast, abrogation of T-cell immunity by alpha mouse thymocyte globulin completely nullified the IFN-dependent therapeutic effect in Meth A-bearing mice. Furthermore, the IFN-dependent therapeutic response in Meth A tumors was much weaker in T-cell-defective BALB/c (nu/nu) mice than that in immunologically competent BALB/c (+/+) mice and was marginal, if present at all, confirming that T-cell immunity was involved in the IFN-dependent therapeutic effect and suggesting that the antiproliferative activity of IFN may only be responsible to a small extent for the therapeutic effect.
Insights
Mouse interferon (IFN) showed therapeutic effects against fibrosarcomas but not adenocarcinoma in mice. T-cell immunity, not direct antiproliferative activity, was key to IFN
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Interferon (IFN) is a cytokine with known immunomodulatory and antiproliferative properties.
- The therapeutic efficacy of IFN in cancer treatment can be influenced by tumor type and host immune status.
- Previous studies suggest IFN's direct antiproliferative effects are a primary mechanism of action.
Purpose of the Study:
- To investigate the in vivo therapeutic efficacy of mouse interferon (IFN) against different murine tumor models.
- To determine the role of IFN's direct antiproliferative activity versus T-cell mediated immunity in its therapeutic effect.
- To correlate in vitro IFN sensitivity with in vivo therapeutic response.
Main Methods:
- Administration of mouse interferon (IFN) to BALB/c mice bearing Meth A, Meth 1 fibrosarcomas, or Colon 26 adenocarcinoma.
- Assessment of tumor growth inhibition following IFN treatment.
- In vitro antiproliferation assays to determine tumor sensitivity to IFN.
- Abrogation of T-cell immunity using alpha mouse thymocyte globulin.
- Comparison of IFN efficacy in immunocompetent versus T-cell-defective (nu/nu) mice.
Main Results:
- IFN inhibited Meth A and Meth 1 fibrosarcoma growth, with minimal effect on Colon 26 adenocarcinoma.
- In vitro IFN sensitivity did not consistently predict in vivo therapeutic response; Colon 26 was most sensitive in vitro but least responsive in vivo.
- Abrogation of T-cell immunity completely abolished the IFN-dependent therapeutic effect in Meth A tumors.
- IFN's therapeutic effect was significantly reduced in T-cell-defective mice compared to immunocompetent mice.
Conclusions:
- The therapeutic effect of mouse interferon (IFN) in vivo is significantly dependent on T-cell mediated immunity.
- Direct antiproliferative activity of IFN may contribute only minimally to its overall therapeutic efficacy against these tumors.
- Tumor type and host immune status are critical factors in determining the success of IFN-based cancer therapy.