Immune Pathways Combine to Refine Response
Signaling pathways work in combination to refine the immune response
Immune balance is maintained through the combination of activating and inhibitory signaling pathways.1,2 Inhibitory pathways can act as safety switches to quickly turn off an immune response.3,4 Inhibition through these pathways can therefore limit the effectiveness of activating signals.5
Immune pathways work in combination to regulate the 3 key stages of the immune response: presentation, infiltration, and elimination.
|Effector T-cell mechanisms|
*Targets are listed by primary mechanisms. Secondary mechanisms may exist.
The immune response is a self-propagating and continuous process. Presentation, infiltration, and elimination are modulated by distinct immune pathways that can function simultaneously or in sequence.6-9
These pathways serve dual roles in regulating the immune response:
- Influence the breadth and magnitude of subsequent stages
- Balance activation and inhibition at each stage
Once an immune response is initiated, each stage can potentiate or limit the activity of subsequent stages. Inhibition of antigen presentation limits the number of activated cytotoxic T cells to infiltrate the tumor and eliminate tumor cells.10 This inhibition can be further perpetuated by inhibitory signals functioning at the tumor cell elimination stage.11,12 Conversely, activating pathways that promote antigen presentation and immune cell infiltration may amplify tumor cell elimination.13
Activating and inhibitory pathways combine to maintain immune balance
Specific activating and inhibitory receptors are present within each stage of the immune response. Because these stages are inherently different, a pathway that regulates antigen presentation may have a different function than one that modulates tumor cell elimination.3,4,11
Tumors can evade the immune response by amplifying inhibitory pathways or suppressing activating pathways.14-16 The way in which activating and inhibitory pathways function together determines the continuation or attenuation of the immune response. Activating pathways can combine to synergistically or additively enhance T- or NK-cell activity.17,18 In contrast, the presence of multiple inhibitory pathways, including immune checkpoint pathways, can amplify the opportunities for tumor cells to evade the immune response.19 Inhibition through these pathways can therefore limit the effectiveness of activating signals.5 When inhibitory and activating signals are both present, the ability to enhance effector cell activity can depend on the scope and strength of inhibition.5
Inhibitory pathways can act either on effector cells or non-effector cells to regulate an immune response. Pathways that function on effector cells can directly modulate antitumor activity.3,4,9,20 Those that function on non-effector cells, including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, support cancer growth by suppressing effector cell activity.6,21-26 Inhibition through pathways on non-effector cells may not completely block immune activity.27 They can, however, extend the inhibitory potential of checkpoint pathways.
Modulating immune pathways in combination may enhance the immune response
Preclinical data suggest that modulation of two immune pathways can more effectively activate immune activity compared with either pathway alone.28-31
At Bristol-Myers Squibb, ongoing research aims to further our understanding of how signaling pathways interact and to identify combination strategies that may activate an effective immune response.
REFERENCES - Immune pathways combine to refine response
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