The assessment of T-cell subsets in response to treatment in patients with breast or oesophageal cancer

Abstract

Background: Cancer is a crippling disease affecting 32.6 million people globally. It is currently ranked as the leading cause of death worldwide, and is associated with significant morbidity and mortality. Despite advances made in the prevention, detection and treatment of malignancy, there remains a dearth of accurate and feasible prognostic and predictive factors for use in the management of patients suffering from cancer in developing countries. It is widely recognized that the immune system plays a fundamental role in regulating the development and progression of malignancy. T-lymphocytes in particular have been categorized into T-cell populations which either promote (T regulatory cells) or prevent (CD4+ and CD8+ T-lymphocyte) cancer development and progression. Aim: The aim of this thesis was to evaluate whether the levels of the respective pro- (T regulatory) and anti- (CD4+ and CD8+ T-lymphocytes) cancer T-lymphocyte subsets before treatment, and alterations of these levels following conventional anticancer treatment (surgery, chemotherapy and radiotherapy) could be used as markers of prognosis in conjunction with other well known prognostic factors, or as predictors of short term (5-7 weeks post-treatment) survival. Methods: Blood samples were collected from 25 breast cancer, and 10 oesophageal cancer patients before antitumor treatment, at day 1 post-treatment and at 5-7 weeks post-treatment. The circulating concentrations and percentages of CD4+, CD8+ and T regulatory cells were determined from whole blood by flow cytometry. These levels were used to determine the CD4: CD8+ T-cell ratio, the CD4+ Treg: total CD4+ Treg ratio and the CD8+ Treg: total CD8+ Treg ratio. Results: Early (stage 1 and 2) HER-2/neu negative breast cancer was associated with a higher CD4+ (558 versus 133 cells/μl; P=0.05) and CD8+ T-cell count (198 versus 58 cells/μl; P=0.05) as compared to early HER-2/neu positive breast cancer. Breast cancer patients showed a significant decline in CD8+CD25+CD127+ Treg cell subsets (P=0.012) following antitumor treatment. However, oesophageal cancer patients showed an increasing trend in CD8+CD127+FoxP3+ Treg cells at day 1 post-treatment (P=0.045) and at 5-7 weeks posttreatment (P=0.044). Patients who demised displayed a significantly lower CD4+: CD8+ Tcell ratio (1.2 versus 2.2; P=0.044) before treatment, as well as a lower CD4+ (111 versus 390 cells/μl; P=0.0046) and CD8+ T-cell count (88 versus 160 cells/μl; P=0.058) at day 1 posttreatment, as compared to those who survived. While patients who survived displayed a higher CD8+ Treg: total CD8+ T-cell ratio (1.48 versus 0.53 P=0.0126) before treatment, and a higher CD4+CD25+CD127+ Treg cell level at day 1 post-treatment (9 versus 2 cells/μl; P=0.047), as compared to those who demised. Conclusion Taken together the findings of this thesis suggest that the CD4+ and CD8+ T-cell count and CD4:CD8 T-cell ratio may serve as predictors of short-term survival in the management of breast and oesophageal cancer. Furthermore, HER-2/neu receptor status may reflect the underlying immune status and antitumor effector activity of a patient. These findings also suggest that T regulatory cell subsets are a heterogeneous group of cells with variable frequencies at presentation and in responses to antitumor treatment depending on the cancer type, stage of disease and antitumor treatment employed. This further illustrates the need for more work aimed at better characterizing the different Treg cell subsets to better identify which subsets are associated with patient prognosis. In summary, this work presents evidence to suggest a role for the T-cell immune profile as a prognostic and predictive parameter in the management of cancer. It argues for early assessments of cancer patients’ immune status as part of the diagnostic work up and that the immune status is taken into consideration when decisions are made regarding treatment.