Curative antitumor immune response is optimal with tumor irradiation followed by genetic induction of major histocompatibility complex class I and class II molecules and suppression of Ii protein

Hum Gene Ther. 2005 Feb;16(2):187-99. doi: 10.1089/hum.2005.16.187.

Abstract

Transfecting genes into tumors, to upregulate major histocompatibility complex (MHC) class I and class II molecules and inhibit MHC class II associated invariant chain (Ii), induces a potent anti-tumor immune response when preceded by tumor irradiation, in murine RM-9 prostate carcinoma. The transfected genes are cDNA plasmids for interferon-gamma (pIFN-gamma), MHC class II transactivator (pCIITA), an Ii reverse gene construct (pIi-RGC), and a subtherapeutic dose of adjuvant IL-2 (pIL-2). Responding mice rejected challenge with parental tumor and demonstrated tumor-specific cytotoxic T lymphocytes (CTLs). We have extended our investigation to determine the relative roles of each one of the four plasmids pIFN-gamma, pCIITA, pIi-RGC, and pIL-2 in conjunction with radiation for the induction of a curative immune response. Upregulation of MHC class I with pIFN-gamma or class II with pCIITA, separately, does not lead to a complete response even if supplemented with pIL-2 or pIi-RGC. An optimal and specific antitumor response is achieved in more than 50% of the mice when, after tumor irradiation, tumor cells are converted in situ to a MHC class I+/class II+/Ii- phenotype with pIFN-gamma, pCIITA, pIi-RGC, and pIL-2. We demonstrate further that both CD4+ helper T cells and CD8+ cytotoxic T cells are essential for induction of an antitumor response because in vivo depletion of either subset abrogates the response. The radiation contributes to the gene therapy by causing tumor debulking and increasing the permeability of tumors to infiltration of inflammatory cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / chemistry
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Survival / physiology
  • Cell Survival / radiation effects
  • Colony-Forming Units Assay
  • Combined Modality Therapy
  • Gene Expression*
  • Genetic Therapy*
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Lymphocyte Depletion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / radiotherapy*
  • T-Lymphocytes, Cytotoxic / immunology
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transduction, Genetic
  • Tumor Cells, Cultured
  • X-Rays

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Interleukin-2
  • MHC class II transactivator protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Trans-Activators
  • invariant chain
  • Interferon-gamma