CXCR5(+) CD8(+) T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma

摘要

Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8(+) T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5(+) CD8(+) T cell is a novel cell subtype and share CXCR5 expression with CD19(+) tumor cells. In this study, we investigated the frequency and function of existing CXCR5(+) CD8(+) T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5(+) CD8(+) T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CDS+ T cells as effector (E) cells and autologous CD19(+) tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5(+) CD8(+) T cell- and CXCR5(-) CD8(+) T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5(+) CDS8(+) T cells presented stronger cytotoxicity than CXCR5(-) CDS8(+) T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5(+) CD8(+) T cells than in CXCR5(-) CD8(+) T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/1L-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5(+) CD8(+) T cells were significantly elevated. Together, these results suggest that CXCR5(+) CDS8(+) T cells are potential candidates of CD8(+) T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression.