There is clear evidence from patients and preclinical cancer models that the adaptive arm of the immune system is involved in controlling the development of malignancies, a process termed tumor immune surveillance. Hence, immunosuppression or –deficiency leads to an increased cancer risk, both in humans and animals. Moreover, spontaneous tumor-specific immunity can be detected in cancer patients and in tumor-bearing mice. However, such anti-tumor immune responses are usually subverted by tumors allowing “uncontrolled” tumor growth. Recent evidence suggests that the immune system not only fails to eliminate established tumors and their metastases but it actually creates a niche enabling a pre-malignant lesion to develop into a tumor which has ”learned” to evade immune surveillance. This kind of “natural selection” leads to the formation of a tumor which actively employs various pathways to block anti-tumor immunity.
The concept of utilizing and manipulating the immune system to control or eliminate tumors is a promising therapeutic option. Over the past ten years, advances have been made in anti-cancer strategies, including the use of immunotherapies and vaccination, with some considerable recent success. However, despite inducing strong systemic anti-tumor immunity, immunotherapies were frequently unable to breach the local barrier created by solid tumors and their microenvironment. Past failures in the translation from preclinical observations towards cancer care in patients are widely held to be due to the fact that the cooperation between basic sciences and clinical medicine was suboptimal. Little attention has been paid to the assessment of multimodal approaches combining the inhibition of key tumor signaling pathways and selective immunotherapy. Thus, a better understanding of the interactions between the tumor, its microenvironment, and the immune system, as well as a better usage of synergies between basic and clinical research - as proposed in this URPP - should strengthen our ability to design new therapeutic strategies focusing on combined regimens and personalized approaches.
Our specific aims are:
1. Evaluation of selected signaling pathways in the tumor microenvironment relevant for tumor immune subversion and their targeting in conjunction with immunotherapy.
2. Assessment of the impact of tumors on their microenvironment and the immune system, leading to immune evasion.
3. Assessment of combination therapies to eliminate autochthonous or established tumorsgraph