New Elements for Immunotherapy Drugs May Improve Their Efficacy

New research from the University of Texas Southwestern Medical Center has discovered new elements to immunotherapy drugs that target programmed death-ligand 1 (PD-L1) on the surface of cancer cells. The findings could offer new targets that may improve how well current cancer immunotherapies work, according to the study.

The FDA approved the checkpoint inhibitor nearly a decade ago. These drugs reverse a cloaking mechanism that many types of cancer cells use to avoid being discovered by the immune system, allowing cancer-fighting immune cells called T cells to attack tumors. Blocking the interaction between 1 of these cloaking proteins, PD-L1, and its receptor on T cell surfaces, forms the basis of several pharmaceuticals currently on the market, including nivolumab, pembrolizumab, and atezolizumab.

Although these drugs have made headway in several types of cancer, notably non-small cell lung cancer (NSCLC)—the leading cause of cancer-associated deaths worldwide—how cancer cells overexpress PD-L1 to shield themselves from immune system attack has been a mystery, according to the study.

The researchers examined which genes might serve as regulators for manufacturing PD-L1 in NSCLC. Using CRISPR gene editing technology, which acts as a molecular scissor to remove specific genes, the researchers individually removed 19,000 genes in a human NSCLC cell line. They then used a fluorescent PD-L1 antibody to see which cells had more or less PD-L1. This allowed them to identify genes that normally encourage PD-L1 production, or positive regulators, and those that stymie PD-L1 production, or negative regulators.

They found that a potent inhibitor for the manufacture of PD-L1 is a gene called UROD that plays a key role in producing heme, an iron-containing chemical that is pivotal for carrying oxygen in red blood cells and necessary in other cells for maintaining homeostasis.

To confirm these findings, the researchers used other methods to remove heme in NSCLC cells, which also triggered the lung cancer cells to make more PD-L1 protein. When tumors with depleted UROD were implanted into healthy models, they grew significantly faster than those in models lacking working immune systems. These findings suggest that by activating PD-L1 production, this gene accelerates cancer by suppressing anti-tumor immunity.

Further experiments demonstrated that hampering heme production turned on a pathway called the integrated stress response (ISR), which cells broadly use to deal with diverse stress conditions such as low oxygen, toxins, or nutrient starvation. Under these conditions, NSCLC cells used a specialized mechanism, relying on a protein known as eIF5B, to increase PD-L1 production. Stimulating cells with this single protein could turn up PD-L1 production, the researchers found, even without tampering with heme synthesis.

In examining a database of genes that are overproduced or underproduced in various cancer, the researchers found that the gene encoding eIF5B is frequently overproduced in lung cancers, and that this overproduction in patients with lung cancer was a marker for poor prognosis.

Developing new drugs that specifically target this protein, or other proteins involved in making PD-L1, could help improve the success of immunotherapy drugs currently in use, according to the researchers.

Reference

• How cancer cells don their invisibility cloaks [press release]. EurekAlert website. Published April 21, 2020. https://www.eurekalert.org/pub_releases/2020-04/usmc-hcc042120.php. Accessed April 30, 2020.