May 15, 2019 02:58 PM EDT
Even though therapies that harness the power of the immune system against cancer have made remarkable progress against certain types of tumors, they remain ineffective in most cancer patients. New research from the Center for Immunology and Inflammatory Diseases (CIID) at Massachusetts General Hospital (MGH) describes a method of reprogramming the regulatory T cells that usually suppress immune responses into inflammatory cells that not only permit but also intensify an antitumor immune response. Their paper is getting an advance online release in Nature.
Senior author of the paper published in Nature, Thorsten Mempel, MD, Ph.D., of the MGH CIID, said that many patients' tumors do not respond to immune therapies such as immune checkpoint blockade because of a lack of pre-existing inflammation that is required for these therapies to work. The researcher's study reveals that reprogrammed Treg cells provide precisely the type of inflammation that is lacking. Indeed, the researchers found in mice that reprogramming tumor-infiltrating Treg cells to secrete inflammatory cytokines makes previously unresponsive tumors highly sensitive to PD-1 blockade.
Also, the MGH study focused on the CBM complex, a large protein cluster within immune cells that helps regulate their activation, proliferation, and function. Recent research has revealed a critical role for the CBM complex in lymphocyte function, and since deleting one of three crucial proteins called CARMA-1 is already known to reduce the capacity of effector T cells, the team examined the effects of CARMA-1 deletion on Treg cells.
The experiment of the team showed that targeting the CBM complex, either by deleting one or both copies of the CARMA-1 gene in Treg cells or by treating tumor-bearing mice with a drug that inhibits MALT1, another component of the complex caused Treg cells to secrete the immunostimulatory cytokine interferon-gamma in tumor tissue alone. The ability to selectively modulate the function to Treg in tumors can avoid the risk of autoimmune disease that would result from system Treg depletion.
Mempel explained that Treg cells are preferential 'auto-reactive,' meaning that they react to human's self tissue antigens. Through reprogramming Treg cells in tumor tissue, the researchers create a local inflammatory autoimmune reaction that primes tumors for immune therapies. Instead of trying to get rid of Treg cells, researchers can now use them as an asset, harnessing their self-reactivity for cancer treatments.
Right now, the team needs to assess whether this approach works as well in humans as it does in mice and understand why Treg cells in the tumor environment, but not elsewhere, are reprogrammed through targeting of the CBM complex. The ability to reprogram Treg cells to improve patient response to immune checkpoint blockade has the potential of increasing the number of patients who can be helped with that approach.
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