The Tumor/Immune Interface: Clinical Evidence of Cancer Immunosurveillance, Immunoediting and Immunosubversion (Report‪)‬

INTRODUCTION The principle that the immune system can recognize and respond to neoplastic cells was first proposed in the 19th century, when William Coley administered killed bacteria (a combination of Streptococcus pyogenes and Serratia marcescens) to sarcoma patients and observed rare, but dramatic, clinical responses[1]. In 1909, the concept of immunosurveillance was hypothesized when Paul Ehrlich proposed that the immune system prevented the outgrowth of carcinomas that would otherwise occur with high frequency[2]. As the understanding of immunobiology expanded, F. Macfarlane Burnett proposed that tumor-specific neo-antigens were capable of eliciting a protective immune response[3] and Lewis Thomas theorized that organisms sufficiently complex and long-lived to be threatened by cancer must possess mechanisms capable of protecting against tumors[4]. Subsequently, physicians have recognized rare spontaneous regressions and remissions in cancer patients[5,6]. In many instances of partial tumor regression, histologic evaluation reveals leukocytes infiltrating tumors, suggestive of an immune mechanism of tumor regression. Furthermore, reports of increased incidence and aggressiveness of a variety of cancers in patients receiving immunosuppressive therapy (e.g., solid organ transplant recipients) or suffering from AIDS have further supported the hypothesis that the immune system plays a critical role in controlling the generation of malignant tumors. In recent years, investigators have recognized the ability of a variety of cells of the immune system to recognize and destroy tumor cells, suggesting a set of cellular mechanisms for tumor immunosurveillance. Enthusiasm over the purported role of the immune system in combating cancer has led to the development of numerous therapeutic agents designed to modulate endogenous immune responses in order to treat tumors; these range from instillation of the mycobacterium Bacillus Calmette-Guerin (BCG) to treat bladder cancer[7] to the use of antibodies targeting negative regulators of immunity such as blocking antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4)[8]. Many such agents are currently in development in a wide array of clinical trials for the treatment of different malignancies.