Effector, memory and naïve CD8+ T cells in peripheral blood and pleural effusion from lung adenocarcinoma patients
Introduction
CD8+ T cells represent a major arm of cell-mediated immune response. These cells recognise and lyse cells carrying non-self epitopes, such as virus-infected cells, grafted tissues or tumour cells. Although genetic, phenotypic and functional studies have been done to assess the pathways of CD8+ T cell differentiation, these have not been fully understood [1], [2], [3], [4]. Whereas the pattern of CD8+ T cell differentiation in the mouse follows the canonical model naïve → effector → memory, in the human several studies [2], [3], [5] have shown the pattern naïve → memory → effector.
The expression of CD45RA or CD45RO isoforms are used to identify naïve and memory CD8+ T cells, respectively. Some reports indicate that within the naïve CD8+CD45RA+ T cell compartment, two distinct subsets can be identified according to CD27 or CD28 expression [1], [2], [3]. Based on these studies, three distinct stages on the CD8 T cell differentiation process can be recognised. (1) Naïve CD8+ T cells are described as CD45RA+CD45RO−CD27+CD28+ cells; this subset produces IL-2 after stimulation, and expresses neither granzymes nor perforin [1], [3]. (2) Memory CD8+ T cells, with CD45RA−CD45RO+CD27+CD28+ phenotype, produce several cytokines after stimulation, and express granzymes but not perforin or express it at a low level [1], [3]. (3) Terminally differentiated (effector) CD8+ T cells, described as CD45RA+CD45RO−CD27−CD28− cells, express granzymes and perforin at a high level [1], [3], [6].
Lung carcinoma is the most common fatal cancer worldwide and adenocarcinoma is the histological type of highest incidence. Pleural effusion is a common manifestation of metastatic lung tumours. Large numbers of pleural effusion mononuclear cells (PEMC) and tumour cells are present in the effusion [7]. Some studies have shown that PEMC exhibit several functional defects [8], [9]. In addition, previous clinical trials evaluating specific and non-specific immune stimulation for the treatment of lung cancer associated to pleural effusion have shown poor results [10], [11].
To our knowledge, there are no reports regarding CD8+ T subsets in lung carcinoma. The aim of this study was to evaluate the frequency of CD8+ T subsets in peripheral blood and pleural effusion from lung adenocarcinomas; in addition, molecules involved in the cytolytic machinery were analysed. Our results show a higher proportion of CD8+ T cells with a memory phenotype and a lower proportion of cells with an effector phenotype in pleural effusion compared to peripheral blood. We found that this phenomenon is not associated to the production of type 2 cytokines by CD4+ or CD8+ lymphocytes; but it might depend on: (1) a block in the terminal differentiation pathway of CD8+ T cells, (2) the early Fas-expression in the naïve CD8+ T subset, which may lead to an increased susceptibility to apoptosis when the naïve cells reach the terminal differentiation stage, or (3) both processes.
Section snippets
Population studied
The population consisted of 13 patients with pleural effusion caused by lung adenocarcinoma. The diagnosis was established by histological examination of pleural biopsy or cytological observation of malignant cells in pleural effusion according to WHO criteria [12]. The malignancy stage was evaluated according to the UICC TNM classification [13] and was as follows: four patients were included in stage IIIb and nine patients in stage IV. All patients were treatment-free. Median age of this group
Proportion of CD3+, CD4+ and CD8+ T cells
In peripheral blood, the percentages of CD3+, CD4+ and CD8+ T lymphocytes from adenocarcinoma patients were not statistically different from those of healthy donors. See Fig. 1.
In lung adenocarcinoma patients, the percentages of CD3+ T cells were significantly higher in pleural effusion (68%, range: 46–90%) than in peripheral blood (43%, range: 33–81%). The percentages of CD4+ T cells were similar in pleural effusion and peripheral blood. In contrast, the percentages of CD8+ T cells were
Discussion
In pleural effusion caused by lung adenocarcinoma, other authors [15], [17] have described an increase in the number of CD3+ and CD4+ T cells with a decrease in CD8+ T cells; our data agree with these observations. In addition, several groups [8], [9], [19] have reported the following defects in immune cells from peripheral blood and pleural effusion of patients with lung carcinoma: (a) reduced proliferation rate, (b) diminished production of some cytokines, (c) reduced capacity of cytotoxic
Conclusions
Tumour microenvironment induces alterations in the CD8+ T cell differentiation program, maintaining it in the memory stage. In contrast to the increased proportion of the memory subset, the proportion of the effector subset is greatly reduced. In addition, the proportion of effector cells producing perforin is also greatly reduced. In naïve cells the proportion of cells expressing Fas is increased. This might lead to apoptosis when the cells reach the effector stage. Although all these
Acknowledgements
This work was supported in part by CONACyT grant F643-M9406. Heriberto Prado-Garcia was supported by CONACyT scholarship 142871.
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