Induction of Novel Tumoricidal Genes Induced by Mm Csf

Jadus, Martin

Abstract

The objective of these studies is to carry out further investigations of the mechanisms underlying the induction of anti-tumor immune responses following interactions between macrophages and tumor cell bearing the membrane form of macrophage colony stimulating factor (mM- CSF). In previous work, the applicants have shown that tumor cells selectively expressing mM-CSF (but not soluble CSF), when implanted in rat brains, are rejected and generated a (presumed) T-cell dependent immune response followed by resistance to challenge with the parental T9 glioma cell line. The observations indicate that mM-CSF transfection leads to both direct tumor rejection and long-term immunity against the parental tumor. The central hypothesis is that macrophages first kill mM-CSF expressing tumor cells through a poorly understood mechanism. The mM-CSF activated macrophages which have phagocytosed the tumor cells then act as antigen presenting cells, stimulating a T-cell dependent immune response and subsequent immunity to the mechanism(s) through which macrophages mediate such anti-tumor responses.
The specific aims are (1) identification of gene products induced within macrophages responding to mM-CSF, using polymerase chain reaction and differential display; (2) cloning and sequencing of selected genes to determine their identify and whether they are unique; and (3) determining whether these gene products play an integral role in the mM-CSF based reactions. The long term goal is to use a similar approach to make tumor cells more immunogenic and thereby stimulate cellular immunity against cancer in humans.