Schlößer, Hans A - CAP 12

Immune checkpoint inhibition (CKI) demonstrated remarkable efficacy in several kinds of cancer, representing a major breakthrough in cancer therapy. These therapies are unique, as the primary target is not the tumor cell itself, but the crosstalk between immune cells and cancer cells in the tumor microenvironment. We described a negative prognostic impact of PD-L1 expression on tumor cells in esophago-gastric adenocarcinoma (EGA) and CKI has been approved as adjuvant and palliative treatment. Despite the promising results, only a minor fraction of patients responds to CKI monotherapy and mechanisms underlying resistance are poorly understood. Successful recognition of tumor cells by immune cells is crucial for therapeutic efficacy of CKI. This recognition depends on a broad spectrum of immune-related tumor cell intrinsic or extrinsic aspects and can so far only be predicted partially by surrogate markers (e.g. mutational burden). Hence, multidimensional analyses of tumor immunogenicity including the immune infiltrate, private and shared neoantigens, tumor specific immune response and immune escape are crucial to further improve therapeutic efficacy and translational research in this field. One key project of our group focuses on tumor-specific endogenous immune response in EGA. Closely related to this project we perform a clinical trial evaluating addition of CKI to neoadjuvant treatment of EGA. The impact of tumor-specific B cell responses on tumor immunogenicity is our second main interest. Overall, we aim to further understand immune escape as key mechanism of primary and secondary resistance to immune checkpoint inhibition.

Our research has immediate translational relevance as endogenous immune response is probably the most relevant factor determining success or failure of emerging immunotherapies. Taken together, our analyses hopefully contribute to an implementation of immunotherapy into treatment algorithms of gastrointestinal cancer, improve translational analyses and support a tailored design of future clinical trials. This could be of similar relevance to cancers of different origins.