Key takeaways: Mesothelioma is associated with mutations in local DNA. These mutations lend themselves to both local and global immunosuppression in mesothelioma patients; oftentimes, patients’ hijacked immunity is more detrimental than the actual tumors themselves. Clinical trials are experimenting with the ability to reprogram natural immune responses.
There is not one consensus among scientists and doctors that establishes the carcinogenesis, or development into cancer, of mesothelioma. Because of its poor prognosis, long latency period, and median age of diagnosis, it has been traditionally difficult for doctors to track the biological and chemical milieus of mesothelioma tumors. By establishing the local immune environments of these tumors–like local resistance to chemotherapy or an increased production of certain proteins–doctors will be able to better understand the growth pathway and consequent treatment of mesothelioma.
Extracellular matrix & stroma
The extracellular matrix (ECM) is a kind of connective tissue that exists between cells: its functions are communication, cohesion, and structural integrity. Healthy ECMs produce communicative proteins and aid in the repair of damaged tissues. Cancers are almost always associated with mutations in DNA, and mesothelioma is no different: DNA that codes for the thickness and integrity of the ECM are upregulated. This means that the ECM, which is usually associated with healthy intercellular communication and integrity, becomes a kind of “insulator” for cancerous cells. Healthy immune responses, then, cannot reach the cancerous cells, contributing to mesothelioma’s resistance to treatments and tendency to metastasize. Plus, because ECMs are usually involved in local growth and repair, mutations lend themselves to ECM-assisted tumor growth.
Taken on the more macro level, the stroma is the collection of ECMs surrounding an organ or tissue. Its functions are nearly identical to those of the ECM, but on a larger scale. Instead of being the medium of communication between individual cells, the stroma is the medium of communication between organs. The effect of cancerous cells modified ECM density is amplified in the stroma: the stroma insulates entire organs from immune responses. Formally, this phenomenon is known as an “immune desert.”
Cytokines
Cytokines are a group of proteins classified by their ability to transmit cellular signals. Mesothelioma cells hijack the healthy network of immune-based cytokines via the previously discussed mutations/ECM changes. Instead of highlighting mesothelioma as an antigen for the immune system to destroy, cytokines become a local immunosuppressant. Like ECM and stromal mutations, they interfere with and hamper the normal immune response.
T-regulatory cells
T-regulatory cells (Tregs) are immune cells that assist in warding off chronic inflammation and autoimmune diseases; they maintain the general severity of the immune response. In a significant number of cancers, Tregs are implicated because of their ability to be “programmed” by cancerous cells. In mesothelioma, Tregs are programmed by the secretome (the sum of all secretions–chemicals, proteins, sugars) of tumors. Like the aforementioned, Tregs are implicated in the reduction of the immune response; however, this effect is more global (whereas ECM & cytokine effects are more local to the site of the tumors).
Recent immunotherapy-based clinical trials are targeting Tregs as their source of interest. If Tregs have the capacity to strengthen or diminish the immune response, can they be reprogrammed by an external secretome? Can this external secretome “train” the immune system to target mesothelioma tumors?
Although these treatments are still being tested, they are promising: they’re indicative of an external capacity to train the body’s immunity.
If you or a loved one has been diagnosed with mesothelioma, please call (800)-505-6000. We are here to help you navigate the legal process of filing a claim to receive compensation for your mesothelioma diagnosis. We help mesothelioma victims and their families in Pennsylvania.
Sources: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01366/full https://www.cancer.gov/publications/dictionaries/cancer-terms/def/extracellular-matrix https://erj.ersjournals.com/content/27/6/1086.short
