Effects of the Conventional Antitumor Therapies Surgery, Chemotherapy, Radiotherapy and Immunotherapy on Regulatory T Lymphocytes in Cancer Patients

Background: Several clinical studies have clearly demonstrated that the immune status is one a major prognostic factor for the survival time in cancer patients. However the main clinical problem is to identify the most prognostically important index within the great number of immune parameters. Recently the evaluation of regulatory T (T-reg) (CD4CD25) lymphocyte count and function with respect to the T helper (TH) (CD4) number has been shown to represent the main immune parameters capable of representing the functional status of the anticancer immunity in cancer patients. This study evaluated the influence of the four main conventional anticancer therapies (surgery, chemotherapy, radiotherapy, immunotherapy) on the CD4/CD4CD25 ratio. Patients and Methods: The study included 70 patients. The oncological treatments consisted of surgery in 14, chemotherapy in 36, radiotherapy in 12 and immunotherapy (subcutaneous low-dose, S.C.-low, interleukin, IL-2) in 8 patients. The normal value of the CD4/CD4CD25 ratio was greater then 4.0. Results: Surgery induced a significant decline in the CD4/CD4CD25 mean ratio. Radiotherapy also induced also a dramatic significant decrease in the CD4/CD4CD25 ratio, whereas the effect of both chemotherapy and immunotherapy reflected the clinical response to the treatments. The CD4/CD4CD25 mean ratio was significantly enhanced in the patients who obtained control of the neoplastic growth, whereas it diminished in progressing patients. Conclusion: The commonly used anticancer therapies profoundly modify the levels of amounts of T-reg lymphocytes. Because of the fundamental role of T- reg cells in suppressing the anticancer immunity, thus diminishing survival, the monitoring of the CD4/CD4CD25 ratio could constitute an important clinical index during conventional anticancer therapies to predict the prognosis of cancer patients. Today, it is known that the failure of an effective anticancer immune response in most metastatic cancer patients depends on the generation of several immunosuppressive events, including lymphocytopenia, namely a decline in T helper (TH) lymphocyte number and functions, decreased dendritic cell function, abnormally high blood concentrations of interleukin (IL) -6, IL-10 and transforming growth factor (TGF) -beta and progressively diminished levels of IL-2 and IL-12 (1-7). Moreover, the laboratory evidence of alterations involving immune cell function and the endogenous secretion of cytokines has appeared to show an association with a poor prognosis (8-10). Unfortunately, from a clinical point of view, the major problem is to quantity the impact of a single immune alteration on the prognosis of a neoplastic disease. Therefore, it could be very important to have an immune index, which might represent the end-result of the great number of immune anomalies occurring during the clinical course of the neoplastic disease. Recent immuno-oncological studies have demonstrated the existence within the TH lymphocyte group (CD4) of a subtype of cell expressing the alpha-chain of the IL-2 receptor (CD25), which may suppress the anticancer immune response by blocking both IL-2- and IL-12-dependent cytotoxicity, the so-called regulatory T lymphocyte (T-reg) (11-14). Therefore, the measurement of the T-reg count could constitute an immune index capable of assessing the general status of the anticancer immune response and the antitumor cytokine network in an individual cancer patient, since T-reg cells have been proven to be stimulated by TGF-beta, IL-10 and IL-6 and to determine a diminished endogenous production of both IL-