The Multicellular Tumor Spheroid: A Quantitative Model for Studies of in Situ Immunity

Abstract

Current knowledge of the basic cellular events associated with the immune response to solid tumors is severely limited by the lack of availability of model systems that adequately reflect the complexity of the environment in situ. Thus, while a number of investigators have isolated and partially purified cells and immunoglobulins from tumors for the purpose of testing their effector functions in vitro (this volume), such studies do not directly pertain to the question of whether or not such mechanisms may be operative within the tumor itself. Indeed it is clear from a number of studies that solid tumors differ from dissociated suspensions of tumor cells in a variety of ways apart from obvious differences in geometry. For example, the concentration of critical metabolites such as oxygen and glucose (as well as toxic waste products) is diffusion-limited in solid tumors, resulting in necrotic areas at distances sufficiently removed from the vascular supply (Thomlinson and Gray, 1955; Tannock, 1968). Similar considerations may account for the fact that solid neoplasms have been found to contain an appreciable fraction of tumor cells that progress through the cell cycle either very slowly or not at all (reviewed in Baserga, 1971). These and other factors have been shown to give rise to heterogeneity in the response of solid tumors to experimental radiotherapy and chemotherapy (Gray et al., 1953; Kaplan, 1974), and similar effects of microenvironment on immune responses might be anticipated.