T cell immunity in cancers and infectious diseases

Paradigm of T cell responses

Antigen-specific T lymphocytes are key orchestrators and effectors of nearly all adaptive immune responses. Upon antigen exposure, naive T cells proliferate and undergo differentiation into distinct classes of effector cells. After antigen clearance, a small proportion of long-lived antigen-specific memory T cells remain with the capability to give rise to recall responses, in the event of antigen re-exposure. Functional memory T cells can be detected in humans for decades following acute viral infections or vaccinations. However, in case of antigen persistence (i.e. chronic infections or cancer), T cells develop a dysfunctional phenotype toward a state named “T cell exhaustion” that is thought to limit immunopathology but ultimately leads to disease persistence and progression. Reversing exhaustion is achievable as demonstrated by the introduction of potent immune checkpoint inhibitors into clinical practice. However, these cancer immunotherapies are effective only for some cancer types and select patients, and the benefice of these therapies is usually not lasting. We recently showed that T cell exhaustion solidifies with time and exhausted T cells retain scars of exhaustion even years after termination of chronic antigen stimulation (Tonnerre et al. Nat Immunol. 2021 ; Yates et al. Nat Immunol. 2021). These findings indicate that the molecular mechanisms underlying T cell exhaustion are complex and heterogeneous. A better understanding of the cellular pathways leading to sustained reinvigoration of exhausted T cells is critical. In addition, alternative approaches such as therapeutic vaccination or T cell adoptive transfer therapies can be needed to fully overcome T cell exhaustion.

Our objectives

Our overarching goal is to improve our understanding of T cell responses in human health and diseases, in order to better inform the design and development of more effective immunotherapies and vaccines. More specifically, our aims are:

1. To understand the heterogeneity and plasticity of both functional memory and exhausted/dysfunctional T cell populations.
2. To decipher the communication pathways between antigen-presenting cells (i.e. dendritic cells) and antigen-specific T cells.
3. To identify new targets for sustained reinvigoration of exhausted T cells, as well as novel therapeutic strategies to artificially expand highly functional and proliferative T cell subsets.

Our approaches

We use cutting-edge technologies (i.e. high-dimensional spectral cytometry, spatial transcriptomics and single-cell RNA sequencing), multi-omics approaches and bioinformatics tools to integrate datasets from human cells and tissues (ex vivo) as well as from miniaturized primary-cell co-culture systems (in vitro). Our models use cross-sectional and longitudinal human samples from patients with infectious diseases, cancers, before and after vaccination or immunotherapy.

Want to join us?

We always welcome applications from motivated and talented scientists, coming from all over world and at all levels. If you want to discuss about potential job openings, feel free to shot an email directly to pierre.tonnerre(“at”)inserm.fr