Study Offers Clues on Why PD-1 Therapies May Fail

The hedgehog signaling pathway may block a crucial step

Kick-starting the body’s immune system to fight cancer has been a promising approach among researchers—but it doesn’t always work. Ohio researchers report a discovery that helps explain why some tumors lack immune-cell infiltration and are therefore unresponsive to therapies that target programmed death-1 (PD-1).

PD-1 is a checkpoint protein on T cells, a type of immune cell that helps the body recognize abnormal cells and disease in the body. PD-1 normally acts as an "off switch" that helps keep T cells from attacking other cells. PD-1 inhibitors are part of a class of drugs known as monoclonal antibodies that are used in oncology to selectively block this protein and boost immune response to attack cancer cells.

Previously reported data have shown that a primary reason some cancer patients do not respond to PD-1 therapy is the inability of the fighter T cells (known as CD8 T cells) to invade the tumor microenvironment, a state also known as "cold tumors."

The new study was published in the Journal of Clinical Investigation by Yiping Yang, MD, PhD, and colleagues at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. They report data showing the specific cellular mechanisms that limit the ability of CD8 T cells to infiltrate the tumor microenvironment. They show that Hedgehog signaling shut down chemokine secretion by tumor-associated macrophages, which is critical to CD8 T-cell infiltration. By blocking (inhibiting) the Hedgehog pathway, the researchers were able to reverse the process and promote CD8 T-cell infiltration into the tumor microenvironment.

"Our data show that Hedgehog inhibitors given in combination with a PD-1 blockade were more effective in killing cancer cells than a single agent alone in preclinical models of both liver and lung cancer," says Dr. Yang, director of the Division of Hematology at Ohio State. "This is an important discovery with the potential to significantly enhance the efficacy of PD-1 therapy and guide new immunotherapeutic strategies in cancer."

The study was conducted in preclinical models of liver and lung cancer. The goal of Dr. Yang and his colleagues is to translate this important discovery from the laboratory to the bedside to benefit cancer patients. The researchers are planning to conduct phase 1 clinical trials using combination strategies in PD-1 and Hedgehog inhibitors for treating patients with lung and liver cancers.

This study was supported by grants from the National Institutes of Health and by a predoctoral fellowship award to first author Amy Petty of Duke University.

Source: Ohio State University Wexner Medical Center, October 23, 2019