Multiple molecular and cellular changes associated with tumour stasis and regression during IL-12 therapy of a murine breast cancer model

Int J Cancer. 1998 Jan 5;75(1):151-7. doi: 10.1002/(sici)1097-0215(19980105)75:1<151::aid-ijc23>3.0.co;2-i.

Abstract

IL-12 treatment of a murine transplantable breast carcinoma (HTH-K) led to tumour regression and cure which was related to the duration of treatment. We studied the sequential molecular and phenotypic changes in IL-12-treated tumours. IFN-gamma mRNA was detected 8 hr after the first treatment. mRNA expression for the IFN-gamma-inducible genes beta 2-microglobulin and indoleamine dioxygenase (IDO) was induced subsequently, together with the chemokine IP-10. IL-12-treated tumours had an abundant cellular infiltrate, consisting mainly of CD8+ T cells. mRNA for granzyme B and perforin also could be detected, suggesting that those cells were activated. After 7 days of daily therapy, tumours in IL-12-treated mice had a significant reduction in vasculature. Finally, the number of apoptotic tumour cells increased throughout IL-12 treatment. We compared the anti-tumour effects of IL-12 to those induced by IFN-gamma therapy, which caused initial tumour stasis but subsequent tumour progression. IFN-gamma induced beta 2-microglobulin and IDO over a 7-day period, but IP-10 was induced only transiently. IFN-gamma caused a lesser cellular infiltrate, a minor anti-angiogenic effect and a transient apoptotic effect. The success of IL-12 may be due to its ability to produce a distinct sequence of molecular and phenotypic changes in tumours, leading to an anti-tumour immune response, toxicity against tumour cells and an anti-angiogenic effect. Other cytokines, such as IFN-gamma, induce some, but not all, of these actions. Comparison of IL-12 and IFN-gamma suggests that sustained induction of IP-10 and activation of a resulting cellular infiltrate may be key changes in regressing tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Granzymes
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-12 / therapeutic use*
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / mortality
  • Mammary Neoplasms, Experimental / pathology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Perforin
  • Phenotype
  • Pore Forming Cytotoxic Proteins
  • RNA, Messenger / metabolism
  • Serine Endopeptidases / metabolism
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes, Cytotoxic / cytology

Substances

  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • RNA, Messenger
  • Perforin
  • Interleukin-12
  • Interferon-gamma
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases