Regulatory T Lymphocytes: Pivotal Components of the Host Antitumor Response

The role of host immunity in the development and progression of cancer has been a subject of speculation and considerable controversy for more than the last 50 years. Tumor-infiltrating lymphocytes (TILs), the primary immune component infiltrating solid tumors, are considered to be a manifestation of the host antitumor reaction. The report by Gao et al in this issue provides additional evidence for the prognostic significance of TILs in solid tumors in general and hepatocellular carcinoma (HCC) specifically. Historically, tumor-associated lymphoid infiltrates were categorized descriptively as brisk, nonbrisk, or absent, based on morphologic observation alone. The survival advantage of a brisk lymphocytic infiltrate in malignant melanoma has been demonstrated by Clark et al, and confirmed by others. However, there is accumulating evidence that the specific type of immune cells, rather than their sheer quantity, governs the host-versus-tumor immune response. With development of immunohistochemical and flow cytometry techniques, it has been demonstrated that the majority of TILs in solid tumors are of the CD3 T-cell phenotype. CD3 T cells can be stratified further into CD4 helper cells (including the Th1 and Th2 subtypes based on their cytokine profile), CD4 regulatory T cells (Tregs), previously designated as suppressor cells, and CD8 cytotoxic effector cells. Initial studies that set out to characterize the antitumor immune response were directed toward CD8 cytotoxic T lymphocytes (CTLs). CTLs destroy tumor cells via the triggering of apoptosis by means of cytotoxic granule exocytosis and/or the Fas/FasL receptor–mediated pathway. In the mid-1990s, antibodies that recognize cytotoxic molecules, including TIA-1, granzyme B, and perforin, became available for immunohistochemical studies. The number of CD8 CTLs expressing TIA-1 and/or granzyme B cytotoxic granules infiltrating tumors has been shown to be associated with improved prognosis in certain human neoplasms, such as Epstein-Barr virus–associated gastric cancer and carcinomas of the colon, breast, uterus, and esophagus. The role of CD4 T cells in the host antitumor response is an area of considerable debate. This subset may be considered as a double-edged immunologic sword, able to promote or inhibit tumor growth. CD4 T-helper cells are subdivided into Th1 cells, which induce cellular immunity, and Th2 cells, which elicit a humoral immune response. The Th1 response is associated with CTL activation and is considered to be beneficial for antitumor immunity. In contrast, a predominant Th2-like cytokine profile is associated with a metastasis-inclined microenvironment in HCC and other tumors. A subpopulation of CD4 T cells, Tregs, which accounts for 5% to 10% of all CD4 cells, is generating intense interest in tumor immunology, autoimmunity, and infectious disease. Historically, Tregs were first hypothesized as suppressive T cells in early 1971 by Gershon and Kondo, however, subsequent studies were hindered because of a lack of specific molecular markers and difficulties in their isolation and culture. The renaissance of these regulatory cells came a few years ago, when FOXP3, a member of the forkhead family of DNA transcription factors, was cloned. There is now considerable evidence that FOXP3 is a key control molecule for Treg development and function, and is an excellent marker for the study of Tregs. Recent studies have demonstrated that Tregs are beneficial for the prevention of autoimmune disease, such as type I diabetes, graft-versus-host disease, transplant rejection, and tissue destruction during infection. In contrast, Tregs seem to be a detrimental factor in the generation of host-versus-tumor immunity via suppression of tumorspecific effector T-cell responses and development of immune tolerance to neoplastic cells. The classic Treg is a thymus-derived CD4 CD25 FOXP3 T lymphocyte. In addition to these markers, Tregs express cell surface CTL-associated antigen 4 (CTLA-4), and the glucocorticoidinduced tumor necrosis factor alpha receptor and secrete immunosuppressive cytokines such as transforming growth factor beta and interleukin 10 (IL-10). Initially it was demonstrated that the number of CD4 CD25 T-cells were increased in several solid tumors and in certain hematologic malignancies. However, subsequent studies provided evidence that CD25, which is an IL-2 receptor subunit, is induced on activation in all T-cells, not just Tregs. Recently, there has been an sudden increase of immunohistochemical studies using FOXP3 as a more specific marker of Tregs. Increased numbers of FOXP3 Tregs infiltrating tumor cell nests have been demonstrated in ovarian, lung, breast, pancreatic, hepatocellular, head and neck, and anal carcinomas, and lymphomas. In most of the solid tumors studied, accumulation of FOXP3 Tregs predicts a striking reduction of patient survival; however, paradoxically, increased FOXP3 Tregs were found to be associated with improved prognosis in lymphoma patients. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 18 JUNE 2