Cancers engage immunosuppressive pathways to promote tumor progression

Tumors exhibit great dexterity to bypass the immune system. Tumor evasion exploits several immunological processes such as the recruitment of immunosuppressive cells (for example regulatory T cells or Tregs, and myeloid-derived suppressor cells or MDSCs), the down-modulation of antigen processing machinery, or the production and release of immunosuppressive mediators (signal proteins and metabolites). Another strategy to inactivate the immune system based on cell-cell interaction involves immune checkpoint system such as PD-1 or CTLA-4. Such targets constitute the inception of immuno-oncology having led to the discovery and the development of immune checkpoint inhibitors as game-changing immunotherapy. Nevertheless such immunotherapies are challenged by different types of resistance.

 

Role of GPCRs in immunosuppression

G-protein coupled receptors (GPCRs) constitute a wide family of cell-surface proteins sensing extracellular signals ranging from proton, to metabolite such as adenosine to large proteins. Upon stimulation, they are engaging specific signalling pathways leading to activation of a diversity of cellular response. All immune cells do express GPCRs and use them to modulate the immune response. As a consequence, many tumors hijacke these GPCR dependant modulatory processes to induce immunosuppression mechanisms underlying tumor evasion.

 

Immunosuppression through Gs-coupled GPCR

Many metabolites produced by cancer cells to promote tumor evasion via immunosuppressive strategy are agonist of Gs pathway coupled to GPCRs. Activation of this signalling pathway leads to an accumulation of intracellular cAMP, an anti-inflammatory messenger, particularly in immune cells such as lymphocytes, neutrophils and eosinophils. cAMP accumulation has multiple consequences including the phosphorylation of the transcription factor CREB (cAMP response element-binding protein) that controls the production of numerous inflammatory cytokines. Examples of metabolites produced by solid cancer and acting on Gs receptor include adenosine, PGE2 or protons (low pH activating specific pH-sensing GPCRs).

 

Immunosuppression through recruitment of immunosuppressive cells

Another key role of GPCRs consists in mediating the chemoattraction of immunosuppressive cells. Indeed, immunosuppressive cells do express specific GPCRs at their cell surfaces which can be used by solid cancers to (chemo)attract them through the overproduction of their endogenous agonists. Example of such ligand/GPCR involved in Tregs attraction includes the CCL1/CCR8, subject of the anti-CCR8 program of Domain.