Cancer Scissors
Researchers from Memorial Cancer Center named after Sloan-Kettering in New York found out how chromosomal instability allows cancer cells to avoid immune protection and metastasize.
During the division of cancer cells, DNA fragments and even entire chromosomes can be duplicated, mutated or lost. This is called chromosomal instability, and scientists have found that it is associated with the aggressiveness of cancer: the more unstable the chromosomes are, the higher the probability that DNA fragments from these chromosomes will end up where they do not belong – outside the cell nucleus, in the cytoplasm.
Cells interpret these DNA fragments as evidence of viral invasion, which leads to inflammation. Immune cells migrate to these cells and secrete protective chemicals. It remained a mystery why this immune reaction caused by cancer cells does not lead to their death.
According to a new study published in the journal Cancer Discovery, the survivability of cancer cells is partly due to a molecule located in the tumor microenvironment that blocks warning signals before they reach immune cells.
The data obtained help explain why some tumors do not respond to immunotherapy, and, equally importantly, suggest ways to increase their sensitivity to immunotherapy.
Detection of dangerous DNA
The warning system that Dr. Samuel Bahum's group studied is called cGAS-STING. When the DNA of a virus or an unstable cancer chromosome enters the cytoplasm of a cell, cyclic GMP-AMP-synthase (cGAS) binds to it, forming cyclic GMP-AMP (cGAMP), which serves as a warning signal. Inside the cell, this signal activates the interferon gene stimulator (STING), which indirectly triggers the transcription of inflammatory genes, providing immune protection against DNA viruses.
In addition, most of the cGAMP moves outside the cell and serves as a warning signal to neighboring immune cells. It activates their immune STING pathway and triggers an immune attack by a virus-infected cell.
Previous work by Bahum's lab has shown that the transmission of cGAS-STING signals inside cancer cells causes them to adopt the properties of immune cells – in particular, the ability to move and migrate, which helps them metastasize. This partly explains how cancer cells survive inflammation and activate metastasis.
A new study shows how cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. The cancer protein ENPP1, like scissors, grinds signals, providing cells with another way to prevent the threat of immune destruction.
Metastatic human melanoma cells in the lymph node. The ENPP1 protein involved in immune evasion is colored green.
The scissor protein ENPP1 covers cancer cells. When cGAMP goes outside the cell, ENPP1 cleaves it and prevents the signal from reaching immune cells. In addition, the destruction of cGAMP leads to the release of adenosine, suppressing inflammation.
In a series of experiments conducted on mouse models of breast cancer, lung cancer and colorectal cancer, Dr. Bahum and his colleagues showed that ENPP1 acts as a control switch for suppressing immunity and metastasis: switching on suppresses immune responses and increases metastasis, switching off activates the immune response and reduces metastasis.
The scientists also studied ENPP1 in human cancer samples; the expression of ENPP1 correlated with both an increase in metastases and resistance to immunotherapy.
Expanding the possibilities of immunotherapy
From a treatment perspective, perhaps the most notable finding of the study is that disabling ENPP1 may increase the sensitivity of some cancers to immunotherapy drugs. In mouse models, researchers have shown the effectiveness of this approach.
The ENPP1 protein is located on the surface of cancer cells, and this facilitates its use as a target for cancer treatment. Disabling ENPP1 will work in two different ways – at the same time, the level of cGAMP outside cancer cells will increase, which activates STING in neighboring immune cells, and also prevents the production of immunosuppressive adenosine. This treatment will also be relatively specific: since most other tissues of a healthy person are not inflamed, drugs targeting ENPP1 will primarily affect cancer.
Several companies are currently developing drugs to suppress ENPP1 on cancer cells. The authors hope that phase I clinical trials of ENPP1 inhibitors will be conducted within a year.
Article J.Li et al. Metastasis and immune evasion from extracellular cGAMP hydrolysis is published in the journal Cancer Discovery.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Memorial Sloan Kettering Cancer Center: Taking the STING Out of Cancer: Discovery about How Cancer Cells Evade Immune Defenses Inspires New Treatment Approach.