Distinct responses of two hepatocellular carcinoma cell lines of a similar origin to immunotherapies targeting regulatory or effector T cells

Abstract

Balance between effector T cells (Teff) and regulatory T cells (Treg) appears to be very crucial for effective anti-tumor immunotherapy. The therapeutic efficacies of enhancement of Teff and suppression of Treg were compared between two murine hepatoma cell lines of a similar origin, MH129 and MH134. Enhancement of Teff was achieved by infection of tumor cells with adenovirus expressing glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), and suppression of Treg, by depletion of CD4+CD25+ naturally occurring Treg by administration of anti-CD25 monoclonal antibody (PC61) or low-dose cyclophosphamide. Our data show that MH129 cells were susceptible to Treg depletion but resistant to GITR expression, and vice versa for MH134 cells. Thus, in MH129 cells, injection of PC61 prior to or after tumor cell inoculation completely or partially, respectively, eradicated tumor growth. Low-dose cyclophosphamide administered after tumor cell inoculation also delayed tumor growth. However, GITR expression either in vitro or in vivo exhibited little effect. In contrast, in MH134 cells, PC61 induced partial tumor growth delay only when injected prior to tumor cell inoculation, and low-dose cyclophosphamide showed no effect, but GITR, particularly when administered in vitro, inhibited tumor growth. An additive effect of PC61 and GITR was observed only in MH134 cells. The ratios of peripheral CD4+CD25+ to CD4+ T cells remained unaltered during the experimental course in both tumor models. From these results we speculate that this different sensitivity may be due to a difference in relative induction levels of Teff versus Treg, not due to different immunogenicity or different kinetics of peripheral Treg, between the two tumor models. Future studies identifying antigen(s) or epitope(s) specific for Teff and Treg in these tumor cell lines are necessary as analysis of the immune response to such antigen(s) or epitope(s) may in general help predict the relative efficacy of different immunotherapies against distinct tumors.