A comprehensive study of effective responses as well as resistant responses to a kidney cancer anti-PD-1 therapy found specific immune features that could provide new targets to improve cancer treatment. The findings were published Feb. 24 in Cancer Discovery.

The researchers, including co-first author Miya Hugaboom, former postgraduate associate in the Braun lab at Yale, co-first author Lena Wirth, immunobiology graduate student in the Braun lab, and senior author David Braun, MD, PhD, assistant professor of medicine (medical oncology) at Yale School of Medicine and Louis Goodman and Alfred Gilman Yale Scholar, studied the tumors of patients who were treated with a drug called nivolumab in a clinical trial. The team collected samples from the patient tumors before treatment and, for some patients, after the patients developed a resistance to the anti PD-1 therapy.

Co-senior authors were Michael B. Atkins, MD, of the Georgetown Lombardi Comprehensive Cancer Center, and Catherine J. Wu, MD, of Dana Farber.

The study used both conventional (bulk) and advanced (single-cell) genetic analyses to understand why some patients responded well to the therapy while others did not. The study identified a group of exhausted immune cells—specifically a type of T cell identified by the expression of specific genes— in the tumors of those who did not respond well. They specifically identified a protein on the surface of these immune cells that impaired their ability to function, and with further study, could potentially represent a target for new therapies. Conversely, the analyses also revealed that those patients who had more B cells (a type of immune cell) and specific tumor immune structures, called tertiary lymphoid structures (TLS), responded well.

“By integrating different forms of advanced analysis, and building it into a clinical trial, we were able to identify some of the key factors that might influence whether a kidney cancer tumor responds (or doesn’t) to current immune-based treatments,” says Braun. “We hope that this work can provide a roadmap for the development of new treatments that build off of these findings.”

Future treatments could target the specific exhausted T cells for elimination, encourage more TLS, or seek to modify the tumor micro-environment to dampen resistance by using these methods to analyze treatment during trials. The study concludes with a recommendation for further study.

This study was supported, in part by the US Department of Defense (grants KC190128/W81XWH-20-1-0882 and KC220016/HT9425-23-1-0735), the National Institutes of Health / National Cancer Institute (1R37CA279822-01), the Louis Goodman and Alfred Gilman Yale Scholar Fund, and the Yale Cancer Center (supported by NIH/NCI research grant P30CA016359).