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Quantitative T cell Immunology and Immunotherapy

Periodic Reporting for period 1 - QuanTII (Quantitative T cell Immunology and Immunotherapy)

Reporting period: 2018-09-01 to 2020-08-31

Health and disease are regulated, to a large extent, by our immune system. The immune system not only protects the body from infectious disease, but is involved in a number of conditions of increasing incidence and morbidity, such as diabetes, rheumatoid arthritis, inflammatory bowel disease and allergies. In cancer, the immune system can be both cause and cure; it contributes to chronic inflammation that promotes tumour development, but it can also provide the ultimate weapon against metastatic disease. Thus, the development of ways to harness, direct or restrain immune responses has great potential for enhancing human health.

Problem addressed by the research project:

Recently, three grand challenges for immunology over the next decade have been identified:
(i) monitoring the immune system in humans in blood and tissues, (ii) clinical translation of methods to modulate the immune system in cancer making use of immunotherapies, and (iii) vaccine development. To this end, new quantitative approaches to query immune cell function in lymphoid organs and tissues are required. QuanTII will address this need by developing novel quantitative methods of (1) the compartmentalisation and dynamics of T cells, (2) T cell receptor (TCR) repertoires in health and disease, in blood and tissues, and (3) T cell immunotherapies.

Why is it important for society?

Results from this project will improve our understanding of (i) immunological memory, (ii) the variety of immune responses evoked by a single pathogen (immune repertoire), and (iii) the molecular and cellular mechanisms at the heart of cancer immunotherapies, such as adoptive cell transfer.

Objectives of the project:

The specific training objectives of QuanTII are: to provide an inspiring and supportive environment for the training of 15 ESRs in Quantitative T cell Immunology and Immunotherapy (QuanTII) and to establish a broad programme of challenging research projects that are multidisciplinary and intersectoral, and lead to lasting, fruitful collaboration between ETN partners.
ESR 1 has obtained fate mapping data of hematopoietic stem cells and followed the propagation of heritable label to double negative (DN) and double positive (DP) thymocyte stages.

ESR 2 has reconstructed the developmental sequence from hematopoietic stem cells via early thymic progenitors to thymocytes and quantified the cell proliferation rates in thymic subpopulations.

ESR 3 has made use of novel algebraic methods, such as Gröbner basis, to study IL-7R binding models to obtain analytical expressions of the steady state, amplitude and EC50 of the dose response.

ESR 4 has started to shed light on the dynamics of senescent CD8$^+$ memory T cells in blood.

ESR 5 has standardised the sorting of memory subpopulation, i.e. T naive, T central memory, T effector memory and T stem cell memory from blood of healthy volunteers.

ESR 6 started her project studying different mathematical models for the cell cycle, with a particular interest in multi-stage representation for cell proliferation via Erlang distributions.

ESR 7 has been trained in isolating cells from tissues and measuring the samples using fluorescence activated cell sorting (FACS) and gas chromatography and mass spectrometry. She is currently preparing for the upcoming TCR repertoire analyses.

ESR 8 has proposed two improvements to estimate the life span of the T cells in the human body using heavy water labelling experiments.

ESR 9 has demonstrated that these results are a consequence of unjustified statistical assumptions and that the data on which they are based do not provide any evidence of an effect of MHC genotype on the oncogenic mutation landscape.

ESR 10 is developing a novel stochastic model of T cell populations in homeostasis including cross-reactivity and multiple self-pMHC complexes.

ESR 11 validated a computational model of TCR probability in the periphery. ESR 11 also applied the method to B cell receptors to check its wide applicability.

ESR 12 is studying the relevance of the iKIR-HLA receptor-ligand system in cancer and autoimmunity and analyse the mechanisms by which iKIRs influence T cells.

ESR 13 aims also to better represent the mechanisms of cancer immune-therapies targeting the immune system to support the development of respective drugs.

The work of ESR 14 started with a comprehensive literature research about pharmacokinetic-pharmacodynamic (PKPD) modelling, which is traditionally based on ordinary differential equations (ODE) and agent-based modelling (ABM), which traditionally is not used in PKPD analysis.

ESR 15 is still working on designing a method to make predictions when two drugs are combined given the effects of individual drugs.
Beyond state-of-the-art: compartmentalisation and dynamics of T cells (WP1).
The success of new vaccination strategies that are currently being developed to trigger responses at the site of pathogen entry, and the success of T cell therapies that aim for a long-lasting effect in cancer patients, depend on the long-term maintenance of naive and memory T cells at appropriate locations in the body. T cells reside in various compartments where they protect against infection. Their major sites of production are lymphoid tissues (thymus, lymph nodes and bone marrow), and yet the vast majority of human data on how these T cells are maintained come from blood samples. An improved quantitative understanding of the in vivo dynamics of the different naive and memory T cell populations throughout the human body and the relationships between them is needed to obtain the best clinical outcome.

Beyond state-of-the-art: TCR repertoires in health and disease in blood and tissues (WP2).
T cell clonotypes can be identified by their unique TCRs, and with current NGS technologies, T cell repertoires can be identified in various tissues for naive and memory T cell subsets. An improved quantitative understanding of the in vivo TCR repertoire diversity and clonal distributions of the different naive and memory T cell populations in blood and tissues, in health and disease, as well as the overlap between and cross-reactivity of these TCR repertoires is needed, not only to obtain the best clinical outcome, but to tailor individual patient T cell immunotherapies.

Beyond state-of-the-art: T cell immunotherapies (WP3).
QuanTII ESRs in WP3 will work to improve our current quantitative understanding of T cell based immunotherapies, by carrying out research projects to develop novel theoretical methods. Adoptive T cell therapies for the treatment of cancer and immunodeficiencies rely on appropriate selection of T cells from the patient, ex vivo clonal expansion through the provision of activating stimuli and, possibly, ex vivo genetic modifications that result in T cells expressing chimeric antigen receptors (CARs). In trials, these CARs are directly engineered to possess a cancer specificity, although some groundbreaking ideas that involve using the natural diversity of other host's TCRs have been proposed.
Group photo from the network meeting, DKFZ, 12-14 February 2020
Group photo from the Inaugural Meeting, Maynooth, 13-17 May 2019
Group photo from the Complementary Skills Workshop, Leeds, 16-19 September 2019