The endothelial barrier. Towards a novel concept for the immunotherapy of cancer

R. Ganss, B. Arnold, G.J. Hämmerling

Division of Molecular Immunology, Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D – 69120 Heidelberg

Remarkable progress has been made in the field of tumor immunology with the identification of tumor antigens, but despite successful activation of tumor-specific T lymphocytes in patients the clinical success is still rather limited. Based on our studies we suggest that the tumor microenvironment prevents eradication of solid tumors by effector cells. Rip-Tag mice develop autochthonous insulinomas in a multi-step process, and, therefore, resemble the clininal situation. Vaccination against the tumor antigen or transfer of tumor-specific T lymphocytes fail to eliminate the tumors. Our findings demonstrate that the tumor endothelium forms a barrier against infiltration by tumor-specific lymphocytes. This appears to be an active mechanism, because the tumor endothelia change their molecular composition in such a way that rolling and sticking of lymphocytes is prevented, the first steps of extravasation. However, induction of inflammatory responses in the tumor and concomitant activation of endothelia, e.g. by irradiation or immunostimulatory CpG oligonucleotides, can overcome this barrier and lead to efficient infiltration of effector cells into the tumor tissue, resulting in destruction of the tumor and survival of the animals.

We suggest that in addition to activation of tumor-specific T lymphocytes the tumor microenviroenment has to be modulated in such a way that T cells can efficiently infiltrate the tumor and maintain their activity. These observations open the way for novel therapeutic interventions.