New Strategy Ups Efficacy of Cancer Immunotherapy

Enzyme found to promote immune suppression by blocking the activation of anti-tumor T cells.

A molecular switch that controls immune suppression could help maximize the efficacy of immunotherapy in cancer, a study published in Nature found.

“Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,” said researcher Judith A. Varner, PhD. “We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”

Normally, when the body is met with pathogens, injury or disease, the initial response of the immune system comes in the form of macrophages, which end up activating T cells to attack the new health threat. The macrophages will then switch gears to express other cytokines that dampen T cell activation, resulting in stimulating tissue repair.

When it comes to Alzheimer’s disease, Crohn’s disease, and other inflammatory diseases, the macrophages associate with the malignancy continue to produce pro-inflammatory cytokines, and other substances that can kill or transform normal cells. For cancer, there are highly abundant microphages that express anti-inflammatory cytokines that induce immune suppression and effectively stops the healing process.

In the new study, researchers were able to identify a key enzyme in macrophages called PI-3 kinase gamma (PI3Ky). The results of the study revealed that macrophage PI3Ky signaling promoted immune suppression by inhibiting the activation of anti-tumor T cells.

When the PI3Ky was blocked, it activated the immune response and caused a significant suppression of tumor growth in the animal models. Furthermore, it boosted the sensitivity of the tumors to available anti-cancer drugs, and also synergized with existing immune therapy to help eradicate the tumors.

Researchers were also able to identify a molecular signature of immune suppression and response in cancer patients and mice that could potentially be used to track the effectiveness of immunotherapy.

“Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body’s own adaptive immune response,” said study co-author Ezra Cohen, MD. “But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors.”

The study built upon previous work from the researchers, who reported that blocking PI3Ky in tumor-associated macrophages stimulated an immune response that results in the inhibition of tumor cell invasion, metastasis, and fibrotic scarring caused by pancreatic ductal adenocarcinoma (PDAC) in animal models.

PDAC is considered the most common malignancy of the pancreas in humans, and is both aggressive and difficult to treat. It is the fourth more common cause of cancer-related death.

“PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed,” said researcher Megan M. Kaneda, PhD, who collaborated on all of the papers.