COLUMBUS, Ohio - Researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) report a discovery that helps scientists understand why some tumors lack immune cell infiltration and are therefore unresponsive to newer PD-1 targeted therapies.
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 has shown that a primary reason some cancer patients do not respond to the 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."
In this new study, Yiping Yang, MD, PhD, and colleagues 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 shows 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 Yang, director of the Division of Hematology at Ohio State and member of the Leukemia Research Program at the OSUCCC - James. "This is an important discovery with the potential to significantly enhance the efficacy of PD-1 therapy and guide new immunotherapeutic strategies in cancer."
Yang and his colleagues report their findings in the Journal of Clinical Investigation.
The current study was conducted in preclinical models of liver and lung cancer. The goal of Yang and colleagues at the OSUCCC - James is to translate this important discovery from the laboratory to the bedside to benefit cancer patients. The researchers are planning to conduct phase I clinical trials using combination strategies in PD-1 and hedgehog inhibitors for treating patients with lung and liver cancers.
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This study was supported by grants from the National Institutes of Health (CA136934, CA186973, CA193167) to Yang, and by a predoctoral fellowship award to first author Amy Petty (CA213799) of Duke University. Additional contributors to this research include Ang Li, Xinyi Wang, Rui Dai, Benjamin Heyman and David Hsu of Duke University, and Xiaopei Huang, PhD, of the Division of Hematology at Ohio State.
Yang came to Ohio State as division director in August 2019 and is a key leader in the Pelotonia Institute for Immuno-Oncology (PIIO). To learn more about the PIIO, visit cancer.osu.edu/PIIO.
About the OSUCCC - James
The OSUCCC - James strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program's 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors and with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, visit cancer.osu.edu.
Journal
Journal of Clinical Investigation