Overcoming obstacles to the effective immunotherapy of human cancer

Cancers can grow and spread in humans despite their expression of cancer-associated antigens and the presence, within the tumor, of immune lymphocytes that can recognize those antigens. One of the possible explanations for this paradox is discussed in the article by Bai et al. (1) in this issue of PNAS. They demonstrate that anti-tumor T cells can be tolerized in the tumor microenvironment and thus down-regulate their effector functions. This is but one element in a complex story. It has been known since the mid-1960s that the cellular arm of the immune response is responsible for the rejection of experimental tumors and organ allografts. The predominant effector element in the cellular immune system is the T lymphocyte, which contains surface molecules called T cell receptors that can recognize antigenic peptides presented on the surface of tumor cells. Thus, attempts to develop effective immunotherapies for cancer have emphasized the stimulation, in vivo, of T cells capable of recognizing and destroying cancer cells that express these antigens (reviewed in ref. 2) These attempts at immunotherapy fall into three main classes. They are (i) nonspecific immune stimulation with the goal that T cells reactive against the cancer will also be increased; (ii) active immunization of the tumor-bearing host designed to increase and activate the numbers of preexisting anti-tumor T cell precursors; and (iii) adoptive cell transfer (or adoptive immunotherapy), which involves the transfer to the tumor-bearing host of activated immune T cells capable of recognizing and destroying …