Understanding and targeting the suppressive function of the ARHGEF1 pathway to unleash T cell immunity against cancer

Cancer is a leading cause of illness and death worldwide. There were an estimated 19.3 million new cases of cancer and 10.0 million deaths in 2020. Cancer death is often preceded by prolonged periods of illness causing distress to patients and carers. There is an urgent need for improved treatments for cancer.

T cells are specialised immune cells that can recognise and kill cancer cells but their function is often suppressed in tumours through a process known as cancer immunosuppression. Releasing T cells from immune suppression using medicines that target the so-called immune checkpoints, CTLA-4 and PD-L1, results in very effective clinical responses in some patients receiving treatment. However, these therapies only result in long-lasting responses in a minority of cancer patients and types of cancer. There is a need to identify other ways the immune system is suppressed in cancer if we are to build upon early successes in cancer immunotherapy for the benefit of the majority of patients who presently do not respond.

Research conducted within our laboratories has identified a new suppressive pathway operating within T cells, dependent upon a signalling protein called Rho Guanine Nucleotide Exchange Factor 1 (ARHGEF1) which restricts T cell function and limits their ability to eliminate cancer. The suppressive function of ARHGEF1 also limits responses driven by immune checkpoint inhibitors. The purpose of this work is to understand how ARHGEF1 suppresses immunity to cancer and immunotherapy responses, to understand the signals received by T cells which drive its suppressive function, and to determine how the ARHGEF1 pathway can be targeted to improve cancer therapy.

Our proposed research is organised into three aims:

Firstly, using new mouse genetic models allowing ARHGEF1 to be disrupted within T cells, we will test how ARHGEF1 functions to suppress immune responses to primary and metastatic solid cancers. We will test whether targeting of ARHGEF1 improves adoptive cell immunotherapy or synergises with existing immune checkpoint inhibitor therapies for cancer.

Secondly, using cutting-edge new experimental techniques for studying biological processes at the molecular level, we will look at the molecular interactions that cause ARHGEF1 to suppress T cell functions. We will determine the function of ARHGEF1 in human T cells.

Thirdly, we will define the extracellular signals and receptors which activate the suppressive function of ARHGEF1 in mouse and human T cells, identifying new targets for immunotherapy.

These studies will define a new suppressive pathway which operates within T cells to limit immunity to cancer and immunotherapy responses. The research will define molecular targets for development of new immunotherapies that act alone or in conjunction with existing immune checkpoint inhibitors to improve therapeutic outcomes for patients with cancer.

Cancer is a major cause of illness and death worldwide. There is an urgent need for improved treatments for cancer. The immune system can recognise and kill cancer cells but its function is powerfully suppressed within tumours. Releasing T cells from immune suppression by targeting immune checkpoints such as CTLA-4 and PD-L1 has revolutionised the way we treat cancer patients. However, only a minority of patients with a subset of cancers robustly and durably respond to existing immunotherapies, termed immunotherapy resistance. There is a need to identify and therapeutically target distinct mechanisms of cancer immunosuppression if we are to build upon early successes in the field of cancer immunotherapy for the benefit of the majority of patients who presently do not respond.

We have discovered a new T cell-intrinsic suppressive pathway, dependent upon the activity of the guanine nucleotide exchange factor, ARHGEF1, which restricts T cell-mediated anti-tumour immunity and responses to immune checkpoint blockade therapy. This research will:

1. Determine the T cell-intrinsic function of ARHGEF1 in suppressing anti-tumour immunity and immunotherapy responses, examining whether the ARHGEF1/RhoA pathway can be targeted to synergise with existing checkpoint inhibitors and improve adoptive immunotherapy

2. Determine molecular mechanisms by which ARHGEF1 suppresses T cell signalling and effector functions, and characterise the function of ARHGEF1 in human T cells

3. Define the extracellular ligands and receptors that drive the suppressive function of ARHGEF1 in mouse and human T cells, identifying new immunotherapy targets

These studies will define a new suppressive pathway operating within T cells to limit anti-tumour immunity and immunotherapy responses. We will define targets for development of new immunotherapies that act alone or in conjunction with existing immune checkpoint inhibitors to improve therapeutic outcomes for cancer patients.