Global Role of the Immune System in Identifying Cancer Initiation and Limiting Disease Progression (2005)

The field of tumor immunology has undergone a significant scientific evolution during the last decade. We now know that human cancer is immunogenic, and we have identified a multitude of tumor-related proteins that stimulate immunity in cancer patients. Highly quantitative and reproducible methods for measuring immunity have been developed and have allowed a more complete delineation of the tumor-associated immune response. Functional antitumor immunity requires a response initiated by potent antigen-presenting cells, such as dendritic cells, and the engagement of a variety of effector cells—not only cytotoxic T cells, but also T-helper cells and B cells, which initiate antibody immunity. Finally, mechanisms of immune escape increasingly are being determined. Cancer evasion of the immune system is not only related to immunosuppressive factors secreted by the tumor and surrounding stroma, but is also aided by the fact that most tumor antigens are self-proteins. Self-proteins, as cancer antigens, impede the generation of robust immunity via toleragenic mechanisms, such as the elaboration of T-regulatory cells, which function to prevent autoimmunity and limit inflammation. The result of these advances in the laboratory is the development of immunotherapeutic strategies that are targeted, are tailored for specific disease burdens, and directly address mechanisms of immune system failure. The studies presented in this issue of the Journal of Clinical Oncology represent the diversity of clinical applications that are now possible when contemplating immune-based strategies for cancer patients. There is abundant evidence that tumor-specific immunity is present even in early-stage cancers. Human antibodies specific for tumor-related proteins, which are used to probe expression libraries developed from tumor cells, are an effective tool for identifying antigens. Recent data suggest that antibody immunity is so prevalent in cancer patients that an immunologic signature that would predict those who will develop cancer can be identified. Screening sera from prostate cancer patients and controls against 22 immunogenic peptides derived from prostate cancer tissue was a more sensitive test than the measurement of serum prostate-specific antigen levels for discriminating individuals with cancer from controls. Furthermore, evidence of an adaptive immune response at the site of a tumor has been shown to impact prognosis. Zhang et al demonstrated that infiltrating T cells observed in ovarian cancer tumors could be characterized as intratumoral or stromal. Those patients with T cells clearly invading the tumor bed had a significantly improved prognosis as compared with individuals whose T-cell infiltrates were located in the stroma. This survival benefit transcended optimal surgical debulking, a critical outcome predictor in ovarian cancer. Analysis of inflammatory infiltrates in non–small-cell lung cancer, presented in this issue of the Journal, demonstrates striking similarities to the observations in ovarian cancer, albeit with a measure of an innate immune response: the macrophage. Macrophage infiltrates could be detected in both tumor islets and the tumor stroma of non–small-cell lung cancers. Increasing macrophage density in tumor islets was an independent favorable prognostic indicator, whereas increasing macrophage stromal density was an independent predictor of reduced survival. The survival benefit associated with macrophage-infiltrating tumor cell islets was discernable even in those patients who had an incomplete resection of their tumor. These patients had a longer survival than those patients whose tumors were completely resected and had evidence of only low intratumoral macrophage infiltration. Such studies lay the foundation for diagnostic and prognostic approaches utilizing VOLUME 23 d NUMBER 35 d DECEMBER 1