Transforming growth factor-β released by PPD-presenting malignant mesothelioma cells inhibits interferon-γ synthesis by an anti-PPD CD4+ T-cell clone

Besides acting complexely on both normal and tumor cells, transforming growth factor-β (TGF-β) can determine the nature of the response to the antigen, strongly inhibiting the differentiation of naive CD4+ T-cells toward a T helper-1 (Th-1) phenotype; in a number of experimental models, TGF-β also appeared to be a potent immunosuppressant factor. TGF-β was shown to be released by some human malignant mesothelioma (MMe) cells, which affects the immune response to this tumor. Thus, for a better understanding of the role of TGF-β in the immune response to MMe cells, we evaluated the production of a Th-1 cytokine (IFN-γ) and of a Th-2 cytokine (IL-4), following Purified Protein Derivative (PPD) recall antigen presentation by human MMe cells to a class-II major histocompatibility complex (MHC-II)-matched PPD clone (PPD clone). Our data confirm that human MMe cells possess the unusual capability of presenting a common recall antigen to CD4+ lymphocytes but also show that these tumor cells can abrogate Th-1 immune response, as evidenced by a shift in favor of the production of IL-4 over that of IFN-γ, through a TGF-β-mediated pathway; only the simultaneous block of TGF-β1 and β2 effects can significantly restore a typical Th-1 pattern of cytokine production by PPD clone in response to PPD presentation by MMe. Even though the role of TGF-β in the promotion of MMe growth should be further and better defined, this effect should be considered when designing new therapeutical approaches aimed at improving the immune response to MMe.