Drug combination overcomes barrier to effective melanoma immunotherapy

April 12, 2018, Ecole Polytechnique Federale de Lausanne
Macrophages can be targeted to improve melanoma immunotherapy. Credit: M. De Palma (EPFL).

Immunotherapies are treatments that stimulate a patient's immune cells to attack tumors. They can be very effective in melanoma—a common and aggressive form of skin tumor—but nonetheless fail in the majority of patients. To address this, researchers are trying to identify the factors that enable successful immunotherapy, as well as those that may limit it. The ultimate goal is to open new avenues for immunotherapies that are more broadly effective in melanoma and potentially other cancer types.

Certain immune cells, called CD8 T cells (or cytotoxic T lymphocytes), can recognize and kill , and thus have the potential to eradicate tumors. Immunotherapies stimulate the CD8 T cells to attack tumors more vigorously. But the activity of CD8 T cells can be suppressed by other immune cells present in tumors.

Studying a subset of patients, researchers led by Michele De Palma at EPFL and Daniel Speiser at the University of Lausanne have identified as the culprits driving resistance to a leading immunotherapy, PD-1 checkpoint blockade.

"The existence of that either execute or suppress cytotoxic immune responses is essential for limiting the potentially deleterious effects of an uncontrolled , a condition that may lead to autoimmunity or organ damage," says De Palma. "The problem is that tumors hijack these regulatory mechanisms to their own benefit, so that they can grow largely unchecked by the immune system."

By analyzing samples obtained from the patients' tumors, Speiser and his colleagues found that the CD8 T cells release signals that indirectly attract the macrophages to the tumors, establishing what they refer to as a "dangerous liaison" in melanoma.

CD8 T cells (red) infiltrate a melanoma. Credit: M. De Palma (EPFL)
"It is a sort of vicious cycle," says Speiser. "The good side of the coin is that the CD8 T cells get activated by certain antigens and initiate a potentially beneficial immune response against the tumor. The bad side is that, when activated, the CD8 T cells also induce the production of a protein in melanoma called CSF1, which attracts the macrophages." Indeed, melanomas that attract many CD8 T cells frequently contain many macrophages, which can weaken the efficacy of PD-1 immunotherapy.

Once recruited en masse to the tumor, macrophages suppress the CD8 T cells and dampen the anti-tumoral immune response. But when the scientists used a drug to eliminate the macrophages in experimental models of melanoma, they found that the efficacy of PD-1 checkpoint blockade immunotherapy was greatly improved.

The findings support the clinical testing of agents that disrupt macrophages in combination with PD-1 immunotherapy in patients whose melanomas contain high numbers of both CD8 T cells and macrophages. "As opposed to targeted therapies that hit specific oncogenes responsible for the growth of the tumor, immunotherapies largely lack biomarkers that can predict whether a patient will respond or not to the treatment," says De Palma.

"Our study suggests that assessing the abundance of macrophages and the contextual presence of CD8 T-cells—for example by measuring genes that are specifically expressed by these —may serve to stratify patients who are amenable to more effective immunotherapy combinations," says Speiser.

Explore further: Who might benefit from immunotherapy? New study suggests possible marker

More information: Natalie J. Neubert et al, T cell–induced CSF1 promotes melanoma resistance to PD1 blockade, Science Translational Medicine (2018). DOI: 10.1126/scitranslmed.aan3311

Related Stories

Who might benefit from immunotherapy? New study suggests possible marker

January 16, 2018
While immunotherapy has made a big impact on cancer treatment, the fact remains that only about a quarter of patients respond to these treatments.

Targeting blood vessels to improve cancer immunotherapy

April 12, 2017
EPFL scientists have improved the efficacy of cancer immunotherapy by blocking two proteins that regulate the growth of tumor blood vessels.

Rare melanoma type highly responsive to immunotherapy

January 11, 2018
Desmoplastic melanoma is a rare subtype of melanoma that is commonly found on sun-exposed areas, such as the head and neck, and usually seen in older patients. Treatment is difficult because these tumors are often resistant ...

Researchers uncover novel mechanism by which tumors evade cancer immunotherapies

November 10, 2017
A Ludwig Cancer Research study led by Benoit Van den Eynde, Director of Ludwig Brussels, has identified a novel mechanism by which tumors of the aggressive skin cancer melanoma can resist cancer immunotherapy. Their paper, ...

Drug combination may improve impact of immunotherapy in head and neck cancer

September 21, 2017
Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers ...

Recommended for you

Pancreatic cancer genetic marker may predict outcomes with radiation therapy

October 22, 2018
Pancreatic cancer is one of the most difficult cancers to treat and is a leading cause of cancer-related deaths. Now, Sidney Kimmel Cancer Center—Jefferson Health and Lankenau Institute for Medical Research scientists find ...

RNA thought to spread cancer shows ability to suppress breast cancer metastasis

October 22, 2018
Researchers at The University of Texas MD Anderson Cancer Center have discovered that a form of RNA called metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to suppress breast cancer metastasis in mice, ...

Revealing the molecular mystery of human liver cells

October 22, 2018
A map of the cells in the human liver has been created by University Health Network Transplant Program and University of Toronto researchers, revealing for the first time differences between individual cells at the molecular ...

New tool gives deeper understanding of glioblastoma

October 22, 2018
Researchers in the lab of Charles Danko at the Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature ...

Targeting a hunger hormone to treat obesity

October 22, 2018
About 64 per cent of Canadian adults are overweight or obese, according to Health Canada. That's a problem, because obesity promotes the emergence of chronic diseases such as type 2 diabetes, heart disease and some cancers.

New drug combination destroys chemo-resistant blood cancer

October 22, 2018
Researchers from The Ottawa Hospital and the University of Ottawa have developed a promising targeted strategy to treat chemotherapy-resistant acute myeloid leukemia (AML) and a diagnostic test to determine which AML patients ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.