Title: Elucidating molecular and cellular mechanisms underlying T-cell dysfunction and effective anti- cancer T-cell responses: towards the development of next-generation immunotherapy
Funder: Cancer Research UK

Abstract: T-cells play central roles in cancer immunity. Notably, immune checkpoint inhibitors show their efficacies through activating T-cells, and/or inhibiting FOXP3-expressing regulatory T-cells (Treg), which suppress anti-cancer immune responses. Particularly, anti-PD-1 antibodies such as nivolumab, which inhibit PD-1 signalling in T-cells, are remarkably effective for advanced-stage melanoma and other cancer patients, inducing anti-cancer T-cell responses. However, the majority of patients still do not respond to immunotherapy by unknown reason. CD8+ T-cells are direct effectors to cancer but are often dysfunctional in cancer patients. PD-1 signalling inhibits T-cell receptor (TCR) signalling and suppresses anti-cancer CD8+ T-cell responses, which can be restored by PD-1 blockade. However, it is not clear which T-cell subpopulations are activated by PD-1 blockade. The lack of this basic knowledge hampers the development of effective strategies for combinatorial therapy. Thus, it is urgently required to obtain a mechanistic understanding of the action of the immunotherapies. PD-1 blockade may work through CD4+T-cells as well, although the underlying mechanism is still not clear. Treg are a promising target for immunotherapy, but Treg-depletion can induce autoimmunity, and it is needed to specifically target cancer-reactive Treg. In addition, PD-1 blockade can enhance Treg activities by unknown reason. Thus, understanding the mechanisms underlying PD-1-mediated T-cell dysfunction and Treg-mediated suppression in cancer is critical for developing new methods to enhance anti-cancer T-cell responses. Aim We will investigate mechanisms of anti-cancer T-cell responses, focusing on activation and differentiation mechanisms of cancer-reactive CD4+ and CD8+ T-cells and their negative regulators including Treg-mediated suppression and PD-1-mediated T-cell dysfunction. The major hypothesis is that, while TCR signals are essential for anti-cancer T-cell responses, chronic TCR signals induce transcriptional mechanisms that control T-cell dysfunction and Treg activities, inducing PD-1 and FOXP3, generating the negative regulator T-cells that inhibit anti-cancer T-cell responses. Methods We will perform immunological experiments using murine melanoma models, single cell technologies (including single-cell RNA-seq) and our new technology, Timer of Cell Kinetics and Activity (Tocky), which reveals temporal dynamics of antigen-reactive CD4+ and CD8+ T-cells and those of Treg in vivo. How the results of this research will be used The programme is expected to (1) identify new molecular mechanisms of cancer-reactive Treg function, (2) obtain a mechanistic understanding of the action of PD-1 blockade, revealing mechanisms underlying T-cell dysfunction, and (3) show cellular and molecular mechanisms for effective anti-cancer CD4+ T-cell responses in melanoma. These will also provide scientific rationales for combinatorial cancer immunotherapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS