| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所碩士在職專班 === 103 === Abstract
1. Objectives
Immune system plays an important role to eliminate cancer cells. Cancer immunity is a complex mechanism and shows potentials for therapeutic targets. As a traditional model, tumor antigens, captured and processed by dendritic cells, would be presented to effector/memory T cells and cytotoxic T cells, which then recognize and attack tumor cells. Regulatory T cells, however, would repress the other immune cells to prevent excess tissue destruction. Unlike solid tumors, lymphomas are originated from immune system, which might directly influence host immune system and reveal more unpredictable results. Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of adult lymphoma. Analysis of host immune cells may provide useful information for assessing prognosis or possibly clinical management. In addition, poor immune surveillance is expected to influence on tumor progression. In human beings, brain is an immune-privileged sanctuary, which may contribute to an ineffective host anti-immune response. Therefore, we focused on a specific DLBCL subtype-primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL) and compared it to peripheral counterpart.
2. Methods
Peripheral blood samples from 77 DLBCL patients and 30 healthy volunteers were analyzed using flow cytometry immunophenotyping. Complete blood cell counts, T cell subsets, and dendritic cells (DCs) were detected and the results were correlated with clinicopathologic characteristics. In addition, thirty-two biopsy specimens of PCNSL and 30 specimens of low-stage non-CNS DLBCL from immunocompetent patients formed the study group. The density and distribution of immune cells, including dendritic cells (DC-LAMP+ and S100+), effector/memory T-cells (CD45RO+) and cytotoxic T-cells (granzyme B+), and expression of HLA-DR by lymphoma cells were evaluated immunohistochemically.
3. Results
Compared with healthy volunteers, DLBCL patients had significantly higher leukocyte and monocyte counts (P〈0.001); higher percentages of neutrophils (P〈0.001), “natural” regulatory T cells (Tregs, CD3+Foxp3+, P〈0.001), and immature DCs (CD83−CD1a+, P=0.005); and lower percentages of lymphocytes (P〈0.001) and helper T cells (P=0.038). In univariate analysis, high neutrophil counts (≧6000/μl, P=0.014) and “induced” Tregs (CD4+CD25+, P=0.026) were poor survival factors along with high IPI scores (P〈0.001) and other high-risk clinical parameters. In multivariate analysis, high Tregs retained significance. Suppression of lymphocytes correlated with poor clinical factors; higher natural Tregs correlated with a lower CD4+/CD8+ ratio (P=0.035) and more immature DCs (P=0.055). In PCNSL, patients showed poorer overall survival (P=0.032). Comparing the PCNSL and DLBCL biopsy specimens, the PCNSL cells showed less HLA-DR expression (P=0.003) and there were fewer S100+ cells (P〈0.01), and effector T cells (P=0.026) infiltrating PCNSL versus DLBCL. For PCNSL patients, fewer cytotoxic T cells in the background were a poor prognostic factor (P=0.004). Intratumoral S100+-cell infiltration was positively correlated with T-cell infiltration, and a T-cell rimming pattern.
4. Conclusions
Changes in blood immune cells occur in DLBCL patients. The results also support a suppressive role of Tregs in adaptive immunity and correlate with poor-risk prognostic factors. In PCNSL, the baseline anti-tumor immune response is inadequate compared with non-CNS DLBCL and this response may play a role in poorer prognosis. Adjuvant dendritic-cell and T-cell immunotherapy may further boost treatment responses in PCNSL patients.
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