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Immune Pathways Combine to Refine Response
- Immune balance is maintained through the combination of activating and inhibitory signaling pathways1,2
- Inhibitory pathways can act as safety switches to quickly turn off an immune response3,4
- Inhibition through these pathways can therefore limit the effectiveness of activating signals5
- Immune pathways work in combination to regulate the 3 key stages of the immune response: presentation, infiltration, and elimination6
*
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 sequence7-10 - These pathways serve the following two 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
that infiltrate the tumor and eliminate tumor cells11
- This inhibition can be further perpetuated by inhibitory signals functioning at the tumor-cell elimination stage12,13
- Conversely, activating pathways that promote antigen presentation and immune-cell infiltration may amplify tumor-cell elimination3
- 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 elimination3,4,12
- Tumors can evade the immune response by amplifying inhibitory pathways or suppressing activating pathways, leading to a noninflamed (cold) tumor14-16
- The way in which activating and inhibitory pathways function together determines the continuation or attenuation of the immune response
- Activating pathways can synergistically or additively enhance T- or natural killer
(NK)-cell activity17,18
- In contrast, the presence of multiple inhibitory pathways, including immune checkpoint pathways, can amplify the opportunities for tumor cells to evade the immune response19
- Inhibition through these pathways can therefore limit the effectiveness of activating signals5
- When inhibitory and activating signals are both present, the ability to enhance effector-cell
activity can depend on the scope and strength of inhibition5
- Inhibitory pathways that act on effector cells can directly modulate antitumor activity3,4,9,20
- Inhibitory pathways that act on
non-effector cells (eg, regulatory T cells
,
tumor-associated macrophages, and
myeloid-derived suppressor cells ) support cancer growth by suppressing effector-cell activity,6,21-26 but may not completely block immune activity27
- They can, however, extend the inhibitory potential of checkpoint pathways
- Preclinical data suggest that modulation of 2 or more immune pathways can more efficiently activate immune activity, leading to an inflamed tumor, compared with either pathway alone28-32
- At Bristol-Myers Squibb, ongoing research aims to further our understanding of how signaling pathways interact and to identify combination strategies, such as inhibition of multiple pathways, that may activate an effective immune response
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REFERENCES–Immune pathways combine to refine response
1. Leung J, Suh WK. The CD28-B7 family in