Researchers discover novel cancer immunosuppression mechanism

By combining flow cytometry, single-cell and bulk RNA sequencing and positron emission tomography researchers reveal the mechanisms responsible for tumour immunosuppression. The findings could contribute to the development of novel cancer immunotherapies.

Regulatory CD4+ T cells (T_regs) are responsible for maintaining immune homeostasis and preventing autoimmunity by inhibiting effector T cells. T_regs achieve this using multiple mechanisms, eg, by expressing cell-surface inhibitors, producing inhibitory cytokines, depletion of IL-2 or direct cytotoxicity, to name a few.

Cancer is known to hijack the immunosuppressive effects of T_regs to create a tumour microenvironment that supports tumour progression. T_regs have also been shown to be enriched in many tumours. Despite the success of clinical studies depleting T_regs to drive tumour regression, the adverse effects that these treatments can cause (eg, autoimmunity and allergies) make it important to identify molecular markers associated exclusively with tumour-linked T_regs so they can be targeted specifically.

In their study, Alvisi et al. studied the molecular mechanisms of immunosuppression in T_regs taken from chemotherapy-naive non-small cell lung cancer (NSCLC) patients. To do this they used a 27-colour flow cytometry panel, encompassing markers of memory and effector T cell differentiation, activation, metabolic activity and exhaustion, as well as T_reg markers. The authors also used single-cell and bulk RNA sequencing and fluorodeoxyglucose uptake in positron emission tomography.

They report that when the T cells were profiles using high-dimensional single-cell profiling, the transcription factor IRF4 was specifically expressed by a subset of intratumoural T_regs with superior immunosuppressive activity. According to the study, these IRF4+ T_regs expressed a vast array of immunosuppressive molecules, compared to their counterparts not expressing IRF4. The presence of these IRF4+ T_regs also correlated with multiple exhausted subpopulations of T cells.

Using transcriptomic and epigenetic data, the team were able to demonstrate that IRF4 alone, or in combination with its partner BATF, can control the expression of a molecular programme responsible for immunosuppression in tumours.

In a murine model, deletion of IRF4 exclusively in T_regs resulted in delayed tumour growth. Correspondingly, an abundance of IRF4+ T_regs is associated with poor prognosis in patients with various cancers. Thus, the team concluded that a common mechanism may be the cause of immunosuppression in the tumour microenvironment, irrespective of the tumour type, and therefore could be targeted by novel therapeutics.

The study was published in The Journal of Clinical Investigation.