Investigation of intratumoural T cell differentiation and function

• Applicant: Lisa Rausch
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506557677

CD8+ T cells exposed to persistent antigenic stimulation in tumours undergo a process called “exhaustion”, during which they lose effector function and upregulate inhibitory receptors, such as programmed cell death 1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) [1, 2]. In the past decade, immunotherapies such as inhibitory receptor (immune checkpoint) blockade were successfully developed that alleviate T cell inhibition and enhance anti-tumour responses, resulting in improved overall survival or even cure for some but not all patients [3, 4]. Exhausted T cells are heterogeneous and comprise at least two distinct populations, including precursors of exhausted T (TPEX) cells and exhausted effector T (TEX) cells [2, 5-7]. Critically, TPEX cells have stem-like properties, continuously self-renew, give rise to TEX cells and are essential for the response to PD-1 checkpoint inhibition [2, 6-17]. However, their precise mode of action and their relative contribution to solid tumour control remain elusive. In addition to exhausted T cells, tumours contain tissue-resident memory (TRM) cells that have been associated with improved prognosis [18-26]. Thus, intratumor T cells form a dynamic cellular network consisting of cells with specialised phenotypes and functions. However, the precise relationships between the individual components of this network and their specific functions are poorly understood. Furthermore, tools are missing that would enable unambiguous identification of exhausted T cell subsets or TRM cells within the tumour environment. Prof Kallies and his group have developed a novel mouse model, the Hobit/Tomato/Id3/GFP double reporter mouse (unpublished data, Kallies lab), that allows the clear detection and characterisation of different CD8+ TILs (tumour infiltrating lymphocytes) based on the expression of the TRM cell-specific transcriptional factor Hobit [24, 27] and the TPEX cell-specific transcriptional regulator Inhibitor of DNA binding 3 (Id3) [7, 10, 14]. The project aims to characterise the function and fate of TPEX, TRM and TEX cells within the tumour environment, identify novel regulators of intratumorally T cells and test the impact of different immunotherapeutic interventions on these processes. Understanding the intratumorally T cell network will provide an important foundation to improve the clinical efficacy of T cell-based therapies, including immune checkpoint inhibitors.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Dr. Axel Kallies