Team TONNERRE

Cellular Immunity in Cancers and Infections

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The ATIP-Avenir team “Cellular Immunity in Cancers and Infections” investigates T-cell responses in cancer and infectious diseases. We aim to define how T-cell heterogeneity and plasticity shape protective and pathological immune responses, and how these properties can be leveraged to improve immunotherapies and vaccines. Using patient cohorts, innovative experimental models, and state-of-the-art multi-omic approaches, we dissect the cellular and molecular mechanisms underlying T-cell activation, differentiation, and function. Our research is highly translational and builds on close collaborations with academic, clinical, and industrial partners.

Scientific context and challenges
Antigen-specific T cells are central players in adaptive immunity. Following antigen recognition, naive T cells proliferate and differentiate into various effector populations. A fraction of these cells persists as long-lived memory T cells, capable of generating rapid and effective responses upon re-exposure to antigen. In humans, these memory T cells can be detected several decades after an acute viral infection or vaccination. In contrast, under conditions of chronic antigenic stimulation — such as during chronic infections or cancers — T lymphocytes progressively acquire a dysfunctional phenotype known as T-cell exhaustion. This state, initially protective in limiting immunopathology, ultimately leads to failure of immune control and disease progression. Although immune checkpoint inhibitors have demonstrated that it is possible to partially restore the functions of exhausted T cells, these approaches benefit only a fraction of patients and their efficacy is often transient. Our recent work has shown that T-cell exhaustion consolidates over time and leaves lasting imprints that persist even after the cessation of chronic antigenic stimulation (Tonnerre et al. Nat Immunol. 2021; Yates et al. Nat Immunol. 2021). These results underscore the complexity and heterogeneity of the molecular mechanisms involved in T-cell exhaustion. In this context, a better understanding of the cellular pathways enabling durable T-cell reactivation is essential.
Furthermore, alternative approaches, such as adoptive cell therapies, are needed to overcome profound exhaustion or to reconstitute impaired or depleted lymphocyte compartments.

Experimental approaches
The team relies on multi-omics approaches to study human T lymphocytes and their interactions with the microenvironment, directly ex vivo or using miniaturized in vitro co-culture systems. Our models are based on cross-sectional and longitudinal human samples from patients with cancers (diffuse large B-cell lymphoma, bladder cancer, hepatocellular carcinoma) or viral infections (influenza, viral hepatitis), collected before and after immunotherapy or vaccination. These integrated approaches allow us to explore human immune responses with unprecedented spatial, functional, and molecular resolution.