Defining the metabolic and functional features of exhausted CD8 T cells

• Applicant: Dr. Anna-Maria Globig
• Subject Area: Gastroenterology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433327376

Immunotherapy is a novel approach in cancer therapy which leverages the body’s immune system against cancer. CD8 T cells are one major component of the body’s natural anti-tumor response. However, chronic antigen exposure leads to a defined phenotype of CD8 T cells with a high expression of inhibitory receptors, an altered transcriptional profile and a severely reduced functionality but also very distinct metabolic characteristics. This specific state of T cell differentiation has been termed T cell exhaustion. As a consequence of T cell exhaustion, anti-tumor immunity is impaired. One strategy of immunotherapy is Immune Checkpoint Blockade (ICB) which targets inhibitory receptors and thereby leads to reinvigoration of exhausted CD8 T cells.Melanoma is the fifth most common form of cancer in both men and women in Germany. Until very recently, patients suffering from advanced melanoma had a very poor prognosis. However over the last few years, immunotherapy has massively improved the survival of these patients. Nevertheless, a significant fraction of patients still does not respond to available immunotherapies or only responds briefly. Thus, novel targets for immunotherapy are urgently needed Recently, the crucial role of metabolism for T cell differentiation and function has been highlighted and differences between naïve, functional effector and memory T cells in fundamental metabolic processes have been well documented. T cell metabolism, function and differentiation state in general have been demonstrated to be closely intertwined and thus also the differentiation state of T cell exhaustion shows very distinct metabolic alterations. This implicates that correcting the metabolic defects of exhausted T cells could help overcome the exhaustion. However, one major gap in our current knowledge is the question which specific genes are responsible for the development of the functional and metabolic characteristics of exhausted T cells.The goal of the proposed project is to advance our understanding of the metabolic defects in exhausted T cells with a focus on the role of mitochondria, ultimately providing potential new targets for immunotherapy in cancer patients. The underlying hypothesis is: The correction of metabolic defects in exhausted cells can potentially correct their differentiation and thus revert exhaustion.I aim to achieve this by performing a genome-wide CRISPR screen and subsequent in vitro and in vivo validation steps in a mouse melanoma model to identify genes in CD8 T cells that are relevant for the formation of metabolic and functional alterations in T cell exhaustion. Since mitochondrial changes have been demonstrated to occur very early in the development of T cell exhaustion and constitute very prominent yet until now insufficiently therapeutically addressed features of exhausted T cells, I will especially focus on CD8 T cell genes that are relevant for mitochondrial function and that also promote effector functions.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Susan Kaech