Researchers Reveal How Tumors Manipulate Certain Immune Cells to Their Own Advantage

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Pictured: Activated macrophage

This scanning electron microscopy image shows an infection-fighting cell called a macrophage. Some macrophages that are located in tumors appear to help cancers grow. (Credit: Steve Gscheissner/Science Photo Library)

Memorial Sloan Kettering researchers have uncovered the origins of a mysterious population of immune cells living within tumors and discovered how the tumors manipulate these cells to their own advantage.

The possibility of harnessing a patient’s own immune system to attack tumors was first proposed more than 100 years ago but has only very recently become a reality. Striking clinical trial results have shown that drugs that unleash the immune system’s T cells can successfully treat several different types of cancer, including late-stage metastatic melanoma. This and other successes prompted Science magazine to name cancer immunotherapy the top Breakthrough of the Year in 2013.

Now the push is on to discover novel immunotherapies that are even more effective. But the relationship between tumors and the immune system is complicated. Many different types of immune cells are found within tumors. For example, some types of T cells have the potential to attack tumors, while other immune cell populations seem to help cancers grow. Immunologist Ming Li at Memorial Sloan Kettering is investigating how the immune system responds to tumors and how the different immune cells that colonize solid tumors interact to influence cancer’s growth and spread.

Subverted Defense

In a new study published in Science, Dr. Li’s team zeroed in on immune cells called macrophages that are found scattered throughout solid tumors. In healthy tissues, macrophages are an essential first-line defense against infection, but tumor-associated macrophages (TAMs) appear to help cancers grow.

“Although several clinical studies show that patients with higher numbers of tumor-associated macrophages have a poorer prognosis, we do not know where these cells come from, what exactly they might be doing to promote tumor progression, or how to stop them,” explains Dr. Li.

Using a mouse model of breast cancer, his team explored the origins and molecular makeup of TAMs. They discovered that TAMs develop from white blood cells that migrate into tumors as they begin to grow and then proliferate there. The development of TAMs depended on the activation of a molecular signaling pathway called Notch.

When the researchers knocked out a critical gene in this signaling pathway, the development of TAMs was inhibited, while the number of T cells within the tumors capable of killing cancer cells increased and tumor growth was suppressed. They propose that TAMs may aid tumor growth by turning off cancer-killing T cells that enter the tumor.

“Based on what we know about conventional macrophages, we were surprised to find that TAMs divide and rely on Notch,” says first author and graduate student Ruth Franklin. “Our findings indicate that TAMs are very different to the nondividing macrophages that populate healthy breast tissue and suggest ways to specifically target these cells for tumor immunotherapy.”

The team is now testing whether these findings hold true for human TAMs. If so, immunotherapies that inhibit TAMs could be a powerful approach to unleash tumor-attacking T cells, particularly if used in combination with other T cell-directed immunotherapies.

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Benefits Beyond Cancer

Because the molecular fingerprint of TAMs is so different from that of macrophages that live in healthy tissues, Dr. Li suspects these cells represent a new type of immune response that may be important in other diseases.

Although macrophages that suppress T cells are bad news in cancer, in some situations they could be beneficial. For example, during chronic infections, excessive T cell activity can cause collateral damage to the body’s healthy tissues. Recruitment and proliferation of T cell–suppressing macrophages within tissues may have evolved as a way of protecting tissues from the immune system.

As tumors grow, they may in turn evolve ways to recruit and co-opt these specialized macrophages in order to ward off tumor-attacking T cells. To test this theory, the group is now exploring whether TAM-like cells arise during infections and in other disease settings.

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My father just had a craniotomy on Friday and yesterday 4/27/16 got the news that it is a glioblastoma grade 4. He will be starting chemotherapy and radiation immediately. In in the medical field and I know this is a fatal cancer. I heard Sloan Kettering has trials that they are running with success, but not sure if he would fall into the trial category considering the type of cancer he has. Any information would be greatly appreciated. He is only 58 years old, never smoked, never drank. He is a health nut and takes very good care of his body. Right now I'm just making sure he stays as healthy as possible, vitamins and organic foods. I need help. Please please please where can I go to get him more help?

Paula, we’re sorry to hear about your father’s diagnosis. MSK has a number of trials for glioblastoma. If you’d like to learn more, you can call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. The oncology nurses who staff the phone line will be able to answer your questions about clinical trials. Best wishes to you and your family.

My dad has recently been diagnosed with adenocarcinoma of esophagus and squamous cell on brain they did lung biopsy to see where squamous is coming from being pet ct scan showed uptake in liver stomach esophagus brain and both lungs. HELP! I buried my mother 3 years ago for non small cell lung cancer that spread everywhere she made it thru 1 round of chemo, I can't lose my dad too I'm 34 a single parent and he is the closet thing my kids know to a real father! I'm a mess they told us no cure palliative treatment to prolong life. There has to be something else

Dear Kate, we are so sorry to hear about your dad’s diagnosis. If he would like to make an appointment with one of our specialists to discuss his treatment options, please call our Physician Referral Service at 800-525-2225. They can answer your questions and arrange for him to see the most appropriate physician for him. To learn more about becoming a patient at MSK, please visit https://www.mskcc.org/experience/become-patient/appointment. Thank you for reaching out to us.

I was diagnosed with Melanoma in 2014. It was a mole in my ear. I had MOSE but it came back. My left ear, parotid gland, and lymph nodes on my left side were removed. There were still microscopic cells along the cut line so I had Radiation Treatments. I had CT/PET Scans every 3 months. I'd have a clean scan then a bad one and more Lymph nodes were removed. I've had 6 surgeries, they just kept removing it. Then I had a PET/CT that showed 2 spots and they started Immunotherapy. I had 4 treatments with Keytruda then a scan that showed 5 more places appeared. It seems to be staying in my Lymph Nodes. The Keytruda wasn't working so it was stopped. I am now on an Infusion of Optivo and Yurovoy. I've had 2 treatments. They want me to have to more with both drugs then drop the Yurovoy and stay on the Optivo. That is if the Scan after the 4th treatment looks promising. If it's still progressing, they say there aren't any other Immunotherapy drugs for me because I have N-ras Mutation not Braf Mutation. Do you know of any other Immunotherapy drugs, other than Interferon, that are available if you don't have the Braf Mutation? Are you doing any trials with Melanoma? I have no other health problems other than the Melanoma. Thank you for your time. Cindy

Dear Cindy, we are sorry to hear about your diagnosis. We are investigating new immunotherapies and other novel treatments for people with melanoma. You may be interested in learning more about our clinical trials for people with an NRAS mutation: https://www.mskcc.org/cancer-care/clinical-trials/search?keys=NRAS&dise…. If you have any questions about these studies or would like to make an appointment, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

My niece has her2 stage 4 metastatic breast cancer, currently with a lung tumor. She has had chemo, radiation. brain surgery, mastectomy. I am interested in knowing more about immunotherapy.

Dear Phyllis, we are sorry to hear about your niece’s diagnosis. We are currently investigating the use of immunotherapy and other novel treatments in people with breast cancer in clinical trials. You may browse through these studies here: https://www.mskcc.org/cancer-care/types/breast/clinical-trials?keys=imm…. If your niece has any questions about these trials or would like to make an appointment, please ask her to call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.