Immune haematology

The study find that immune system against cancer have made remarkable progress against certain types of tumors; therefore they still remain ineffective in most cancer patients. A new study 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.

The regulatory T cells

Their paper is receiving advance online release in Nature.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 those therapies to work;” says Thorsten Mempel, MD, Ph.D., of the MGH CIID, senior author of the Nature paper.

“Their  study shows that reprogrammed Treg cells provide exactly the type of inflammation that is lacking. Indeed, we found in mice that reprogramming tumor-infiltrating Treg cells to secrete inflammatory cytokines makes previously unresponsive; tumors highly sensitive to PD-1 blockade.” The MGH study focused on the CBM complex a large protein cluster within immune cells that helps regulate their activation; proliferation and function.

Secrete inflammatory cytokines

Recent research has revealed a critical role for the CBM complex in lymphocyte function, and since deleting one of three key proteins, called CARMA1, is already know to reduce the function of effector T cells; the team examined the effects of CARMA1 deletion on Treg cells.

Their experiments revealed that targeting the CBM complex either by deleting one or both copies of the CARMA1 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.

Inflammatory autoimmune reaction

The ability to selectively modulate the function of Treg in tumors can ; avoid the risk of autoimmune disease that would result from systemic Treg depletion.”Treg cells are preferentially ‘auto-reactive;‘ meaning they react to our own, ‘self’ tissue antigens,” explains Mempel; an associate professor of Medicine at Harvard Medical School.

“By reprogramming Treg cells in tumor tissue, we create a local inflammatory autoimmune reaction that primes tumors for immune therapies. So instead of trying to get rid of Treg cells, we now can use them as an asset; harnessing their self-reactivity for cancer treatment.”CBM targeting led to inflammation of tumor tissue and increased infiltration by cytotoxic CD8 T cells and natural killer cells.

But it only reduced the rate of tumor growth in mouse models of melanoma and colon cancer because the activity of those immune cells was still limited by the immune checkpoint protein PD-1. However; blocking the activity of PD-1 with antibodies led to elimination of tumors that had been inflamed by anti-CBM treatment.