Immunotherapy can fire up a protein that disables a T cell attack

Lung cancer immunotherapy triggers a counterattack by a surface protein found on the tumors of some patients that stifles the immune system's assault, researchers at MD Anderson Cancer Center report in Cancer Discovery.

Their research shows in detail how the protein, called CD38, reaches out to disable attacking immune system T cells and points to a variety of drugs that could counter CD38's defenses. One such combination already is in clinical trial.

"We've shown that CD38, historically best known as a surface protein on immune system cells and a therapeutic target in multiple myeloma, plays an active role on solid tumors, shutting down immune response in immunologically 'hot' tumors that are undergoing immune attack," says senior author Don Gibbons, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology.

"There are a number of ways we might translate these findings in the clinic, because there are three categories of drugs under development that aim at targets we've identified," Gibbons says. "We're working on that now."

Immune checkpoint blockade drugs block activation of PD-1, a checkpoint protein on T cells that turns T cells off, providing durable responses in about 20 percent of non-small cell lung cancer patients. Antibody drugs either block PD-1 directly on T cells or inhibit the PD-L1 ligand found on tumors and other tissues that turns on PD-1.

MD Anderson researchers are trying to understand how to extend response to more patients and identify biomarkers to indicate who should receive anti-PD1 immunotherapy.

The team's paper was one of two in Cancer Discovery from MD Anderson identifying major immunotherapy resistance factors. A second paper uncovered the importance of STK11/LKB1 mutations.

CD38 stands out as resistance develops

The team analyzed gene expression among mice treated with anti-PD-L1 antibodies whose tumors developed resistance after five to seven weeks and found that only CD38 was prominently expressed among 200 differentially expressed genes.

• When they cultured cancer cells with activated T cells, they found increased production of CD38 on the tumors that was further enhanced by PD-L1 treatment.
• The attacking T cells and the resulting inflammatory environment produce all-trans retinoic acid (ATRA) and interferon-beta, which activate CD38 on the tumors.
• CD38 drives adenosine production, which connects to receptors on the T cells to suppress their function.

Having established these connections in cancer cell lines and mouse models, the team analyzed human tumors, finding CD38 present on 15 percent and 23 percent of early stage lung cancer patients in separate cohorts comprising 793 patients.

Gene expression data from three lung cancer data sets and one melanoma data set showed high levels of CD38 on 25-30 percent of tumors, strongly correlated with an immune inflammatory signature that includes multiple markers of immune-suppressing cells or checkpoint molecules.

Combination overcomes resistance

Treating mice with a combination of anti-PD-L1 and an anti-CD38 antibody stifled both primary and metastatic tumors.

Adding anti-CD38 to mice after their tumors developed resistance to anti-PD-L1 enhanced attacking T cell responses and reduced populations of regulatory T cells and myeloid-derived suppressor cells, two types of immune cell that inhibit immune response.

While their research focused mainly on lung cancer with some analysis of melanoma, their data suggests the CD38 resistance mechanism could be present in other tumor types in response to T cell infiltration and inflammation. "We're studying other tumor types now," Gibbons says.

An anti-CD38 antibody called daratumumab is approved for treatment of multiple myeloma, a cancer of plasma cells. Other CD38 inhibitors are in development, along with drugs that block CD73, a downstream molecule that synthesizes adenosine, and adenosine receptor inhibitors.

Any of those drugs is a potential partner with anti-PD-1 or anti-PD-L1 to overcome CD38-related resistance, Gibbons says.

One phase 1 clinical trial under way at MD Anderson pairs a CD38 inhibitor with an anti-PD1 antibody for patients with advanced lung or prostate cancers, whose tumors have previously responded, but progressed on immunotherapy.