Marco Frentsch - CD8+ T cell-derived CD40L mediates cytotoxicity against cancer cells

Exploiting T-cell therapy is emerging as one of the most effective treatment options to combat malignancies. However, which subset and functional quality of CD8+ T cells is more suitable for achieving effective and durable responses in the strong immunosuppressive context of cancer is still a matter of debate and investigation. We detected recently that in average 25% of human memory CD8+ T cells express CD40L, a strong immunostimulatory molecule of activated CD4+ T helper cells that is even able to overcome cancer-induced immunosuppression. Therefore, we analyzed the role of this distinct CD8+ T-cell population in antitumor responses.

First, we assessed the expression of CD40L on CD8+ T cells in a tumor model where B6 mice were challenged with SV40 TAg-expressing cancer cells. Here CD40L+CD8+ T cells represented up to 50% of the protective tumor-specific CD8+ T-cell response. To analyze the impact of CD40L expression on CD8+ T cells in vivo we challenged Rag1-/- mice with cancer cells and adoptively transferred wt or CD40L-/-CD8+ T cells. Application of wt CD8+ T cells prevented the formation of solid tumors, whereas transfer of CD40L-/-CD8+ T cells alone or together with wt CD4+ T cells resulted in a non-controlled tumor progression. The necessity of CD40L on CD8+ T cells for tumor rejection was further demonstrated by injecting cancer cells in mice that lack CD40L expression only on mature CD8+ T cells. This newly generated E8Icre x CD40Lflox mouse strain was significantly more susceptible to tumor formation than wt mice. Since the injection of the cancer cells in complete CD40L-/- but not in CD40-/- mice resulted in tumor formation, we assume that CD40L-mediated rejection does not depend on interaction with CD40+ host cells but more on CD40 expression by the injected cancer cells.

Further, we could observe that many human and murine carcinomas and melanomas express CD40 and triggering CD40 with multimeric CD40L or CD40L expressing CD8+ T cells induce often programmed cell death in CD40+ cancer cells through caspase 8 activation.

Taken together, our data reveal that the presence of tumor-specific CD40L+CD8+ T cells may represent a crucial element in control and rejection of tumors. Therefore, the capability of CD8+ T cells to express CD40L should be considered in future immunotherapies against CD40+ expressing cancers, which is a common feature among many human cancer entities.

Marco Frentsch - Berlin-Brandenburg Center for Regenerative Therapies (BCRT) - Charité Universitätsmedizin Berlin

1996-2002 Academic studies „Diplom Biochemistry“ at the Free University of Berlin
2002-2008 PhD Graduation at the German Rheumatism Research Center, Berlin
2008-2009 PostDoc at the German Rheumatism Research Center, Berlin
2009-2017 PostDoc at the Berlin-Brandenburg Center for regenerative therapies
2017 Group Leader at the Berlin-Brandenburg Center for regenerative therapies

Specialty and Research Field of Interest : 1. T cell functions; 2. Tumor immunology; 3. Measurement of antigen-specific immune responses