Some cancer cells adapt mechanisms to evade detection and destruction by the host's immune system. One way cells do this is by hijacking normal mechanisms of immune checkpoint control and modulation of the innate immune response via STING.
Immune checkpoints refer to the built-in control mechanisms of the immune system that maintain self-tolerance and help to avoid collateral damage during a physiological immune response. It is now evident that tumors engineer microenvironments to evade immune surveillance and attack, particularly by modulating certain immune-checkpoint pathways.
Tumor-specific T cells must discriminate between destruction of the tumor cell and survival of the target cell. Important for discrimination are proteins on both the T-cell and the target cell:
- CD8 is a T cell and the coreceptor for the T cell receptor (TCR). These two distinct structures recognize the Antigen–Major Histocompatibility Complex (MHC). In tumors, T cells are also known as tumor infiltrating lymphocytes (TIL), present in high abundance at the tumor site to influence overall survival. During cancer therapy, TILs are sometimes removed from a patient’s tumor and are then treated with substances that activate the lymphocytes to help them better kill the patient’s cancer cells.
- PD-L1 and PD-L2 (programmed cell death proteins) are transmembrane proteins that suppress the adaptive arm of the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states like hepatitis. PD-1 on the T-cell is activated by the cell surface ligands on the tumor cell. Upregulation of PD-L1 may allow cancers to evade the host immune system.
- TIM-3 is an inhibitory molecule that is induced following T-cell activation. As a negative regulatory immune checkpoint, it is detected in different types of immune cells, including T cells, regulatory T cells (Tregs), dendritic cells (DCs), B cells, macrophages, nature killer (NK) cells, and mast cells. TIM-3 inhibits antitumor immunity by mediating T-cell exhaustion.
- STING (stimulator of interferon genes) is a key mediator of innate immunity, and the STING pathway has been shown to be involved in the induction of an anti-tumor immune response. STING is responsible for regulation of type-I interferon production and cellular defense against intracellular pathogens (like bacteria or viruses). Key regulators of the STING pathway are:
- Interferon regulatory factors (IRFs) comprise a family of transcription factors that function within the Jak/Stat pathway to regulate interferon (IFN) and IFN-inducible gene expression in response to viral infection.
- STING is a signaling molecule associated with the endoplasmic reticulum (ER) and is essential for controlling the transcription of numerous host defense genes (including type I interferons (IFNs) and pro-inflammatory cytokines) following the recognition of aberrant DNA species or cyclic dinucleotides in the cytosol of the cell. Sting can translocate out of the ER upon activation.
Learn more about the pathways and proteins involved in Avoiding Immune Destruction:
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Select References:
- Hanahan D, Weinberg RA (January 2000). "The Hallmarks of Cancer". Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9
- Hanahan D, Weinberg RA (March 2011). "Hallmarks of Cancer: the next generation". Cell. 144 (5):646-74. doi: 10.1016/j.cell.2011.02.013.
- Yayi He, et al. "TIM-3, a promising target for cancer immunotherapy". Onco Targets Ther. 2018; 11: 7005–7009.
- Barber, Glen N., “STING: infection, inflammation and cancer”. Nat Rev Immunol. 2015 Dec; 15(12): 760–770.