Tumor-specific endogenous immune response in esophago-gastric adenocarcinoma

• Applicant: Privatdozent Dr. Hans Anton Schlößer
• Subject Area: General and Visceral Surgery
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325827080

Esophago-gastric adenocarcinoma (EGA) is the sixth most common cause of cancer related death world-wide with rising incidence. The overall very poor prognosis of this cancer type could be improved by state-of-the-art multimodality treatments combining surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibition (CKI) targeting anti-PD-1 can be considered effective in EGA and has been added to standard treatment algorithms based on very recent data. In August 2021, the European Medicines Agency (EMA) approved the PD-1 inhibitor nivolumab for palliative and adjuvant treatment of EGA. Despite the remarkable clinical results of CKI, objective response rates are usually below 25% and mechanisms underlying susceptibility to CKI are poorly understood. Enhanced endogenous or de-novo induced tumor-specific immune responses are assumed as the major mode of action of CKI. Our project aims to elucidate key principles of anti-tumor immune responses against EGA in previously untreated patients to identify the most important aspects underlying susceptibility to CKI and other immunotherapies in an unbiased cohort. Mutation-associated neoantigens (MANAs) derived from nonsynonymous somatic mutations and de-novo expressed tumor associated antigens (TAAs) are the two major categories of target genes for anti-tumor immune responses. Prediction of MANAs is highly complex and we established a complex pipeline allowing identification of MANAs based on whole-exome sequencing, HLA-genotyping, peptide-affinity prediction, and autologous T cell expansion. Functional assessment of MANA-specific T cell responses is ongoing, and we need a second funding period to appropriately exploit already generated data. Regarding TAAs, we identified the most important TAAs in EGA and analyses of TAA-specific immune responses revealed tumor-specific antibodies in 48% and tumor-specific T cell responses against at least one out of 10 analyzed TAAs in 68% of patients. Strikingly, presence of TAA-specific immune responses was related to absent expression of the respective target genes in 88.2% of tumor samples. This is only one out of several identified immune escape strategies and our renewal proposal aims to elucidate these important mechanisms underlying inefficacy of MANA-/TAA-specific immune responses in EGA. The publications from our first funding period describe tumor-specific B cell responses, antigen-presenting properties of tumor-associated B cells, expression of co-inhibitory molecules in the tumor microenvironment and a correlation of T cell abundance and genes related to antigen-presentation as important novel characteristics of EGA. The experiments planned in this second funding period aim to fully exploit already generated data, to identify key mechanisms of immune escape in EGA and to demonstrate enhanced vulnerability of EGA by targeting of these mechanisms. The recent EMA-approvals for CKI in EGA further increased the translational relevance of our project.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Axel Hillmer