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New Insights into Why the Immune System Fails to See Cancer

Boston, MA— Cancer hides in plain sight of the immune system. The body’s natural tumor

surveillance programs should be able to detect and attack rogue cancer cells when they arise, and

yet when cancer thrives, it does so because these defense systems have failed. A team of

investigators led by Niroshana Anandasabapathy, MD, PhD, at Brigham and Women’s Hospital

have uncovered a critical strategy that some cancers may be using to cloak themselves – they

find evidence of this genetic program across 30 human cancers of the peripheral tissue, including

melanoma skin cancer. Their results are published June 29 in Cell.

“Our study reveals a new immunotherapy target and provides an evolutionary basis for why the

immune system may fail to detect cancers arising in tissues,” said corresponding author

Anandasabapathy, of BWH’s Department of Dermatology. “The genetic program we report on

helps the immune system balance itself. Parts of this program prevent the immune system from

destroying healthy organs or tissues, but might also leave a blind spot for detecting and fighting

cancer.”

The authors studied immune mononuclear phagocytes – a group of disparate cells that act as the

“Pac man” of the immune system. When these cells detect foreign invaders and dying normal

tissues, they devour or engulf their components. These cells then present these components on

their surface teach T cells to maintain tolerance to healthy tissues, or to fight infections and

pathogens. Despite differences in function, all immune mononuclear phagocytes found in the

skin- (a peripheral tissue like lung and gut) share a common set of genetic programming, which

is further enhanced when they enter the tissue. This program is conserved in fetal and adult

development, and across species. And, the research team reports, is co-opted by multiple human

cancers of tissue.

The team finds that this program is prompted by an “instructive cue” from interferon gamma – a

molecule that plays a critical role in regulating immunity. The authors find IFNg is a normal developmental cue for mononuclear phagocytes in development but that IFNg and

tissue immune signatures are much higher in skin cancer than in healthy skin. Having an immune

response measured by IFNg programing and tissue signatures correlated with improved

metastatic melanoma survival outcomes, making these signatures potential biomarkers for cancer

survival.

The authors reasoned such a program might contain key molecules that help the immune system

reduce inflammation, but that might also leave a blind spot to cancer detection. One of the key

genes the researchers detected is suppressor of cytokine signaling 2 (SOCS2). When this gene

was turned off in a mouse model, the immune system was able to robustly detect and reject

cancer in models of melanoma and thymoma (cancer of the thymus). They also observed

improved vaccination responses, and heightened auto-inflammation suggesting this gene

normally dampens auto-inflammatory responses and contracts protective immunity.

“Our research suggests that these cancers are co-opting tissue-specific immune development to

escape detection, but we see that turning off SOCS2 unmasks them,” said Anandasabapathy.

“This sheds new light on our understanding of how the immune system is programed to see

cancers and also points the way toward new therapeutic targets for treating cancers that havethese signatures.”

June 29, 2017 at 12 p.m. noon EDT

Contact: Haley Bridger

Brigham and Women’s Hospital

617-525-6383, hbridger@bwh.harvard.edu

Weill Cornell Medicine Anandasabapathy Lab 413 E 69th St., Rm 920 New York, NY 10021 Phone: 646-962-9970