TGF{beta}-signaling in T cells suppresses Tbet mediated CD4+ anti-tumor immune responses in a murine model of lung carcinoma (P2021)

TGFβ is an important immunosuppression inducing factor in the lung tumor microenvironment and is suggested to facilitate the escape of tumor cells from immunosurveillance. In this project we investigate TGFβ-mediated effects on tumor infiltrating CD4 + T cells, also addressing the question of how TGFβ-induced T cell subtypes, such as Treg and Th17 cells, contribute to tumor cell tolerance. We found an upregulation of TGFβ in patients affected by lung carcinoma. In a murine model of lung carcinoma we also observed a significant reduction of tumor growth as well as prolonged survival of CD2TβRIIdN mice, which exhibit a defective TGFβ-signaling in T cells. This was accompanied by increased numbers of tumor infiltrating effector T cells, reduced induction of Tregs in the tumor tissue and enhanced Th1 cell responses. Similarly, reduced tumor load was observed after intranasal application of anti-TGFβ1 antibodies to tumor bearing wild-type mice. By contrast, Tbet -/- mice showed increased tumor growth. To further analyze the opposing effects of Tbet and TGFβ on CD4 + anti-tumor responses, we crossed CD2TβRIIdN and Tbet -/- mice and found that this newly generated mouse strain was not protected from tumor development. Moreover the results suggest a relation between tumor growth and Th17 cell responses in this context. Together, our data reinforce the importance of Tbet for anti-tumor immune responses and outline the manifold role of TGFβ for lung cancer.