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A central question in cancer immunology is whether a specific anti-cancer immune response fails to develop in a cancer host, or whether a response develops but is impeded or actively suppressed in some way. With recent advances in immunological methods, it is becoming increasingly clear that a specific anti-cancer immune response is often detectable in common forms of human cancer, such as lung cancer [1] , colon cancer [2] , breast cancer 3 , 4 , 5 , melanoma [6] , and chronic lymphocytic leukemia (CLL) [7] . This raises the question of what mechanisms may be operating to prevent effective implementation of the host immune responses to growing malignancies. This review presents a perspective on the evidence that a systematic disorder of CD8+ T lymphocytes could account for the dysfunctional host immune system responses to progressive forms of cancer. In our own studies, monoclonal antibodies (anti-CD11b and anti-CD28), known to enable isolation of human T cell subsets capable of down-regulating immune responses, were used in flow cytometry assays on peripheral blood from patients with various forms of cancer to assess the prevalence and clinical significance of CD8+ T cell subset abnormalities in common human malignancies. In CLL, the presence of abnormally large populations of regulatory or putative immune suppressor T cells (i.e., CD3+/CD8+/CD11b+/CD28-, [Ts]) correlated with rapid disease progression in early-stage cases (N = 14; P = .01). It was also discovered that clinical responses to chemotherapy in four of four cases of CLL involved substantial changes toward normalization of disordered CD8+ T cell subsets. In solid tumors, such as colorectal adenocarcinoma (N = 6) and intracranial neoplasms (N = 7), where the immunological microenvironment of the tumor site may be less well reflected by peripheral blood findings than in cases of leukemia, a trend of abnormally high percentages of Ts cells among CD8+ T lymphocytes was found nevertheless, although the clinical significance of this phenomenon remains to be determined. The results of our pilot study involving early-stage B-CLL cases suggest that the enumeration of CD11b+/CD28- CD8+ T cell subsets could help predict which patients will have a rapidly progressive disease course, and which may have a more indolent form of disease that may not require treatment. Moreover, if these T cell subsets are later proven to have an integral role in the progression of malignancies in human hosts, new immunotherapeutic strategies designed to reduce the numbers or the deleterious function of these T cell subsets may become a successful adjunct to current approaches to treating patients with cancer. |
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