Activated naïve B cells promote development of malignant pleural effusion by differential regulation of T_H1 and T_H17 response

Abstract

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (T_H)1 cells and increased T_H17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase T_H1 cells and decrease T_H17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited T_H17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4⁺ T-cell differentiation into T_H1/T_H17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating T_H1/T_H17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.