Beyond checkpoint inhibitors: Natural killer cells limiting antitumor T cell immunity in hepatocellular carcinoma

• Applicant: Dr. Nathalie Schmidt
• Subject Area: Gastroenterology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323178777

Hepatocellular Carcinoma (HCC) is the sixth most common cancer worldwide with a rising incidence. Due to limited therapeutic options, HCC is the second leading cause of cancer related death. Thus, the development of new therapeutic approaches is of a high clinical relevance to improve patient care. Immunotherapies with the aim to induce or boost tumor-specific CD8+ T cell responses constitute a promising, innovative treatment option for patients with HCC. However, several inhibitory mechanisms contribute to a failure of naturally occurring antitumoral immune responses. In order to develop efficient immunotherapeutic strategies, a thorough understanding of these inhibitory mechanisms is of high importance. To address these inhibitory mechanisms, my work program will be dived into two independent, but closely related topics of HCC immunology. In the first part, the inhibitory potential of natural killer cells (NK cells) will be addressed. In chronic hepatitis B infection, NK cells are an important inhibitor of antiviral CD8+ T cells. Importantly, the mechanisms of T cell failure overlap between HCC and chronic hepatitis B infection, thus, a similar inhibitory potential of NK cells in patients with HCC is very likely. In the proposed research project, a failure of antitumoral T cells caused by a deletion or inhibition by NK cells will be analyzed.The second part of the planned project will focus on the inhibitory receptor programmed death (PD)-1. Targeted therapies blocking PD-1 or its ligand (PD-L1) have shown promising results in first clinical trials. However, the exact immunological mechanism leading to this observed clinical response has not been investigated in patients with HCC, but an induction of antitumoral immune responses is expectable. Thus, for the first time the effect of this immunotherapeutic approach on antitumoral CD8+ T cells will be analyzed. This is of high clinical relevance, because a relevant number of patients fails to respond to this treatment. Thus, especially in patients without clinical benefit of this therapy, we expect additional inhibitory mechanisms, e.g. NK cell/T cell interactions, that will be further analyzed in this special patient cohort.A better understanding of the immunological mechanisms of blocking the PD-1/PD-L1 signaling pathway as well as the analysis of the inhibitory potential of NK cells will facilitate an optimization of immunotherapy. This is of high clinical relevance to improve the care of patients with advanced tumors.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professorin Dr. Mala Maini