People usually mention the immune system when talking about colds or flu. Immune cells do fight viruses and bacteria, but they also destroy abnormal cancer cells inside the body.

“Don’t Eat Me” Signal 101

A white blood cell called a macrophage is part of the innate immune system. It patrols tissues and engulfs infected and cancerous cells.

Cancer cells can hide from macrophages and avoid being destroyed. Most cancer cells display a protein called CD47. When CD47 binds SIRPalpha on macrophages, it sends a “don’t eat me” signal, and the macrophage ignores the cancer cell.

Stanford researcher Irv Weissman discovered this signal. His team showed that an antibody blocking CD47 disrupts the CD47‑SIRPalpha interaction. This antibody turns off the “don’t eat me” signal and restores the macrophage’s ability to kill cancer cells.

Because most cancer cells display CD47, anti‑CD47 antibodies offer a powerful way to target cancer stem cells. These stem cells drive tumor growth and relapse across many cancer types. CIRM is funding three clinical trials testing anti‑CD47 therapy, including one at Stanford and two run by Forty‑Seven Inc., a Stanford spinout. They aim to treat acute myeloid leukemia (AML), as well as colon cancer and other solid tumors.

“Reaching Clinical Trials” does not equal “The Research is Done”

Although clinical trials are underway, the Weissman team continues to study ways to block the CD47 “don’t eat me” signal. They found that while anti‑CD47 increased macrophage killing in most cancer samples, some remained resistant. Responsive samples also varied widely in how much killing increased.

These results suggested other mechanisms help some cancers evade macrophages even when CD47 is blocked. In a Nature Immunology, report, the team identified a second, independent “don’t eat me” signal that could enable more precise therapies.

To find this alternate signal, they first looked for links between cancer type and resistance but found none. They then analyzed surface proteins on cancer samples and discovered that cells with high levels of MHC class I were more likely to resist anti‑CD47 treatment.

A Second “Don’t Eat Me” Signal

MHC class I proteins help the adaptive immune system monitor activity inside cells. They appear on most cells and display internal protein fragments. When T or B cells recognize a fragment as abnormal, they trigger strong killing responses.

Cancer cells use MHC class I as a second “don’t eat me” signal. The proteins bind LILRB1 on macrophages, preventing macrophages from destroying the cancer cells. Blocking either MHC class I or LILRB1 lifts the signal and restores macrophage activity in lab samples and in mice with human cancers.

Co‑lead author Amira Barkal explained the impact of blocking both signals. She said dual blockade drove many immune cells into tumors and significantly increased tumor clearance. She expressed excitement about future therapies that combine multiple blockades to halt cancer growth.

The Big Picture for Cancer Immunotherapies

Because MHC protein class I proteins play an important role in stimulating immune cells called T cells to kill cancer cells as part of the adaptive immune response, the level of MHC protein on an individual patient’s cancer cells could serve as an indicator, or “biomarker”, for what type of cancer therapy to pursue.  The big picture implications of this idea are captured in the press release:

“Understanding the balance between adaptive and innate immunity is important in cancer immunotherapy. For example, it’s not uncommon for human cancer cells to reduce the levels of MHC class 1 on their surfaces to escape destruction by T cells. People with these types of tumors may be poor candidates for cancer immunotherapies meant to stimulate T cell activity against the cancer. But these cells may then be particularly vulnerable to anti-CD47 treatment, the researchers believe. Conversely, cancer cells with robust MHC class 1 on their surfaces may be less susceptible to anti-CD47.”

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