Research Report 2010 - MDC

Thomas BlankensteinStructure of the GroupGroup LeaderProf. Dr. Thomas BlankensteinScientistsDr. Jehad CharoDr. Thomas KammertönsDr. Ibrahim Kocman*Dr. Catarina Leitao*Dr. Liang-Ping LiDr. Joanna ListopadDr. Jan SchmollingerDr. Gerald WillimskyMolecular Immunology andGene TherapyMost of the current experimental cancer models do not reflect the pathophysiology of reallifecancer. Cancer usually occurs sporadically and is clonal in origin. Between tumorinitiation and progression clinically unapparent pre-malignant cells may persist for years ordecades in humans. More recently, mouse models of sporadic cancer have been developed. Themouse germ-line can be engineered with high precision so that defined genes can be switchedon and off in the adult organism, ideally in a locally and timely controlled fashion. However,analysis of the immune response against sporadic tumors requires the knowledge of a tumorantigen.In the last two years our group focused on several areas in cancer immunology. We analysed atwhich point of cancer development T cells become aware of the cancer cells. We asked whetherthe initial recognition of cancer cells by cytotoxic T-lymphocytes (CTL) results in tumor immunityor tolerance. Additionally, we employed different strategies of cellular therapy.Immunogenicity of premalignant lesions is theprimary cause of general cytotoxic T lymphocyteunresponsivenessCancer is sporadic in nature, characterized by an initialclonal oncogenic event and usually a long latency.When and how it subverts the immune system isunknown. We show, in a model of sporadic immunogeniccancer, that tumor-specific tolerance closely coincideswith the first tumor antigen recognition by B cells.During the subsequent latency period until tumorsprogress, the mice acquire general cytotoxic T lymphocyte(CTL) unresponsiveness, which is associated withhigh transforming growth factor (TGF)β 1 levels andexpansion of immature myeloid cells (iMCs). In micewith large nonimmunogenic tumors, iMCs expand butTGF-β 1 serum levels are normal, and unrelated CTLresponses are undiminished. We conclude that (a) toleranceto the tumor antigen occurs at the premalignantstage, (b) tumor latency is unlikely caused by CTL control,and (c) a persistent immunogenic tumor antigencauses general CTL unresponsiveness but tumor burdenand iMCs per se do not.Engineering antigen-specific primary human NKcells against HER-2 positive carcinomasNK cells are promising effectors for tumor adoptiveimmunotherapy, particularly when considering the targetingof MHC class I low or negative tumors. Yet, NKcells cannot respond to many tumors, which is particularlythe case for nonhematopoietic tumors such as carcinomasor melanoma even when these cells lose MHCclass I surface expression. Therefore, we targeted primaryhuman NK cells by gene transfer of an activatingchimeric receptor specific for HER-2, which is frequentlyoverexpressed on carcinomas. We found that these targetedNK cells were specifically activated upon recognitionof all evaluated HER-2 positive tumor cells, includingautologous targets, as indicated by high levels ofcytokine secretion as well as degranulation. The magnitudeof this specific response correlated with the level122 Cancer Research