Researchers identify immune-suppressing target in glioblastoma

Researchers at The University of Texas MD Anderson Cancer Center have identified a tenacious subset of immune macrophages that thwart treatment of glioblastoma with anti-PD-1 checkpoint blockade, elevating a new potential target for treating the almost uniformly lethal brain tumor.

Their findings, reported in Nature Medicine, identify macrophages that express high levels of CD73, a surface enzyme that's a vital piece of an immunosuppressive molecular pathway. The strong presence of the CD73 macrophages was unique to glioblastoma among five tumor types analyzed by the researchers.

"By studying the immune microenvironments across tumor types, we've identified a rational combination therapy for glioblastoma," says first author Sangeeta Goswami, M.D., Ph.D., assistant professor of Genitourinary Medical Oncology.

Glioblastoma immunotherapy clinical trial planned

After establishing the cells' presence in human tumors and correlating them with decreased survival, the researchers took their hypothesis to a mouse model of glioblastoma. They found combining anti-PD-1 and anti-CTLA-4 immunotherapies in CD73 knockout mice stifled tumor growth and increased survival.

"We're working with pharmaceutical companies that are developing agents to target CD73 to move forward with a glioblastoma clinical trial in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors," says Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology.

Sharma and colleagues take an approach they call reverse translation. Instead of developing hypotheses through cell line and animal model experiments that are then translated to human clinical trials, the team starts by analyzing human tumors to generate hypotheses for testing in the lab in hopes of then taking findings to human clinical trials.

To more effectively extend immunotherapy to more cancers, Sharma says, researchers need to realize immune microenvironments differ from cancer to cancer. "Understanding what's different in immune niches across cancers provides clues and targets for treating tumors," Sharma says. "That's why we did this study."

The team tracked down the population of CD73-positive macrophages through a project to characterize immune cells found in five tumor types using CyTOF mass cytometry and single-cell RNA sequencing. They analyzed 94 human tumors across glioblastoma, non-small cell lung cancer and kidney, prostate and colorectal cancers to characterize clusters of immune cells.

CD73 cells associated with shorter survival

The most surprising finding was a metacluster of immune cells found predominantly among the 13 glioblastoma tumors. Cells in the cluster expressed CD68, a marker for macrophages, immune system cells that either aid or suppress immune response. The CD68 metacluster also expressed high levels of CD73 as well as other immune-inhibiting molecules. The team confirmed these findings in nine additional glioblastomas.

Single-cell RNA sequencing identified an immunosuppressive gene expression signature associated with the high-CD73-expressing macrophages. A refined gene signature for the cells was evaluated against 525 glioblastoma samples from The Cancer Genome Atlas and was correlated with decreased survival.

The team conducted CyTOF mass cytometry cluster analysis on five glioblastoma tumors treated with the PD-1 checkpoint inhibitor pembrolizumab and seven untreated tumors. They identified three CD73-expressing macrophage clusters that persisted despite pembrolizumab treatment.

Sharma and colleagues note the prevalence of CD73-expressing macrophages likely contributed to lack of tumor-killing T cell responses and poor clinical outcome.

Combination extends survival in mice

A mouse model of glioblastoma showed that knocking out CD73 alone slowed tumor growth and increased survival.

The team treated mice with either PD-1 inhibitors or a combination of PD-1 and CTLA-4 immune checkpoint inhibitors. Mice with intact CD73 treated with the combination had increased survival over untreated mice, while mice with CD73 knocked out lived even longer after combination therapy. There was no survival benefit from anti-PD-1 alone.

"Based on our data and earlier studies, we propose a combination therapy strategy to target CD73 plus dual blockade of PD-1 and CTLA-4," the team concludes in the paper, noting that anti-CD73 antibodies have yielded promising results in early studies.

Sangeeta Goswami, Thomas Walle, Andrew E Cornish, Sreyashi Basu, Swetha Anandhan, Irina Fernandez, Luis Vence, Jorge Blando, Hao Zhao, Shalini Singh Yadav, Martina Ott, Ling Y Kong, Amy B Heimberger, John de Groot, Boris Sepesi, Michael Overman, Scott Kopetz, James P Allison, Dana Pe'er, Padmanee Sharma.
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma.
Nat Med, 2019. doi: 10.1038/s41591-019-0694-x.

Most Popular Now

Theravance Biopharma and Pfizer Inc. enter global …

Theravance Biopharma Ireland Limited, a subsidiary of Theravance Biopharma, Inc. (NASDAQ: TBPH) ("Theravance Biopharma") and Pfizer Inc. (NYSE: PFE) ("Pfizer") today anno...

Researchers identify immune-suppressing target in …

Researchers at The University of Texas MD Anderson Cancer Center have identified a tenacious subset of immune macrophages that thwart treatment of glioblastoma with anti-...

Intermittent fasting: live 'fast,' live longer?

For many people, the New Year is a time to adopt new habits as a renewed commitment to personal health. Newly enthusiastic fitness buffs pack into gyms and grocery stores...

Pharmacies leave customers hanging when it comes t…

Proper disposal of leftover medication, particularly antibiotics and opioids, can help reduce antibiotic resistance, prevent children from being poisoned and stop the mis...

Researchers determine how a specific protein regul…

Immune checkpoints are surface proteins that cancer cells use to evade immune response. These surface proteins are critical for cancer cell growth and drugs targeting the...

Bristol-Myers Squibb completes divestment of manuf…

Bristol-Myers Squibb Company (NYSE:BMY) announced today that it has completed its previously announced divestment of its oral solid, biologics, and sterile product manufa...

Bayer and Exscientia collaborate to leverage the p…

Bayer and Exscientia Ltd., a UK-based Artificial Intelligence (AI)-driven drug discovery company, have entered into a three-year, multi-target collaboration. The partners...

Scientists find a new use for already known anti-c…

The world scientific community is waging a difficult and prolonged war on cancer. New research in the field of immunogenic cell death can extend the area of drugs applica...

Lynparza approved in the US as a 1st-line maintena…

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) announced that Lynparza (olaparib) has been approved in the US f...

Farxiga granted FDA Priority Review for patients w…

AstraZeneca today announced the US Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) and granted Priority Review for Farxiga (dap...

FDA approves first generics of Eliquis

The U.S. Food and Drug Administration has approved two applications for the first generics of Eliquis (apixaban) tablets to reduce the risk of stroke and systemic embolis...

Aspirin appears to curb colorectal cancer recurren…

The benefits of a daily aspirin may extend beyond heart health to colorectal cancer treatment, say City of Hope researchers who have found aspirin appears to reduce tumor...