How a cancer drug alters the immune system to fight against cancer

A recent study by a team of UChicago researchers sheds light on how venetoclax, a drug commonly used to treat a broad array of cancers, might have effects beyond merely killing tumor cells.

Venetoclax works by blocking a protein called BCL-2, which many cancer cells rely on to survive, forcing tumor cells to undergo programmed cell death or apoptosis. While venetoclax is widely used in cancer treatment, often in combination with chemotherapy or immunotherapy, researchers are now investigating its broader impact on the immune system.

James LaBelle, MD, PhD, Associate Professor of Pediatrics, Director of Pediatric Stem Cell and Cellular Therapy Program at the University of Chicago, and senior author of the new study, is interested in understanding the immunological properties of small molecule therapeutics commonly used to kill cancer cells.

“We have many small molecule therapeutics that target proteins inside cells—many of which weren’t available 20 years ago,” he said. “These drugs are now being used on patients for increasing number of clinical trials, yet most research has focused on their effectiveness in getting rid of tumor cells. We are interested in how these compounds also affect normal immune cells.”

In the case of venetoclax, not much research has been done on its long-term effects on normal cells, particularly immune cell types that depend on the BCL-2 family for their growth and development. Immune cells protect the body from foreign pathogens and abnormal cancer cells, but when overactivated in the wrong context, they can harm healthy tissues and cause autoimmune diseases. Regulatory T cells (Tregs) help suppress this overactivity, keeping the immune response in balance. However, if Tregs become too active, they can hinder the immune system’s ability to fight cancer.

“Tregs are really important, because they dampen immune response against self-antigens,” LaBelle said. “Though, in the context of cancer, that can be bad. If you have lots of Tregs, they can suppress antitumor immune responses originating from within the body.”

While venetoclax is designed to block BCL-2 and induce cell death in cancer cells, Tregs seem to behave differently. Therefore, LaBelle’s team aimed to understand how venetoclax affects Treg function to have enhanced antitumor immunity.

"What we found was surprising," LaBelle said. "Even though venetoclax doesn’t kill Tregs, it alters their behavior, making them less suppressive and more inflammatory. In this context, we induced plasticity changes in Tregs where they can acquire different functionality.”

The changes in Treg behavior were observed at the gene expression level, with cells shifting towards a pro-inflammatory state. The shift led to increased production of inflammation-related proteins in both immune tissues and the tumor microenvironment. The results were even more intriguing.

"Not only did targeting BCL-2 with venetoclax produce this effect, but we also observed it when we genetically knocked out BCL-2. This supports the underlying mechanism that BCL-2 is involved in regulating Treg behavior beyond controlling cancer cell death," LaBelle said.

The team also tested venetoclax in combination with a PD-1 checkpoint inhibitor—an immunotherapy designed to boost T cell function.  That combination showed that venetoclax, while targeting BCL-2, can further enhance antitumor immune responses when used with checkpoint inhibitors.”

LaBelle said there is still much to learn about how BCL-2 proteins influence immune function. “We're eager to explore how venetoclax affects other types of T cells, including adoptively transferred T cells and normal circulating CD4 and CD8 T cells naturally produced by the body," he said.

Looking ahead, LaBelle's team plans to test these findings in clinical trials, particularly focusing on solid tumors. "We’re excited about the potential of combining venetoclax with other treatments, such as checkpoint inhibitors. The promise of this approach lies in its potential to achieve a synergistic effect,” he said.

The study, “Venetoclax Induces BCL-2–Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti–PD-1 Checkpoint Blockade”, was supported by grants from AbbVie-University of Chicago Consortium, Multi-Disciplinary Training Grant in Cancer Research, National Institutes of Health, Jill and John Svoboda, and University of Chicago Comer Development Board.

Additional authors include Rosy Liao, Jocelyn Y. Hsu, Nasa S. Aboelella, Joshua A. McKeever, Anika T. Thomas-Toth, Andrew S. Koh from the University of Chicago.