Protein linked to immunotherapy resistance in kidney cancer
UTSW-led study identifies immune-suppressing protein as a driver of relapse and potential target for new therapies
DALLAS – May 08, 2025 – A protein identified by researchers at UT Southwestern Medical Center may drive resistance to immune checkpoint inhibitors, a widely used form of immunotherapy to treat cancer. The findings, published in Communications Medicine, link glycoprotein non-metastatic melanoma protein B (GPNMB) to relapse after treatment and suggest it may help tumors evade immune surveillance in metastatic renal cell carcinoma.
“Finding serum GPNMB as a predictor of acquired resistance and a potential target for overcoming that resistance to cancer immunotherapy could contribute to further improvement of the outcome of cancer patients,” said study leader Kiyoshi Ariizumi, Ph.D., Professor of Dermatology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.
Checkpoint inhibitors improve survival for many patients with advanced cancers by removing the molecular “brakes” that prevent immune cells from recognizing and eliminating tumors. However, more than half of patients who initially respond to this type of immunotherapy eventually relapse due to acquired resistance within a few months to years of sustained treatment.
To better understand how this resistance develops, UT Southwestern researchers analyzed tumor and blood samples from 39 patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Among patients who initially responded positively, 28% developed resistance within two years, coinciding with rising levels of GPNMB in the blood. By comparing samples collected before treatment and after disease progression, the team investigated the molecular changes that may cause relapse.
Using RNA sequencing and whole exome analysis, the researchers found that GPNMB was significantly upregulated in tumors after relapse. Its increase in blood samples during disease progression raises the possibility of its use as a noninvasive biomarker to track treatment response. If validated, such a blood-based marker could help clinicians identify resistance earlier and adjust treatment accordingly.
The team traced the rise in GPNMB to a signaling cascade set in motion by immune checkpoint therapy itself. That same molecular pattern – which also appeared in the blood of relapsing patients – strengthened the connection between the laboratory findings and clinical outcomes.
In mouse models, blocking GPNMB restored CD8+ T cell activity – a critical component of the immune response – and improved the effectiveness of the therapy after it had stopped working. In another experiment, shutting off the gene that produces GPNMB also resensitized resistant tumors to treatment.
“Our findings have great promise in being able to establish personalized cancer medicine specialized for tumor recurrence and create novel inhibitors that restore tumor response to immunotherapy,” Dr. Ariizumi said.
He and other scientists at UTSW have investigated the role of GPNMB in suppressing immune responses to cancer for years. This new work builds on that foundation by directly linking GPNMB to therapy resistance in kidney cancer. Although the study focused on metastatic renal cell carcinoma, the researchers plan to collaborate with clinical oncologists at the Simmons Cancer Center to explore whether GPNMB-driven resistance also plays a role in other cancers treated with immune checkpoint inhibitors.
Other UTSW researchers who contributed to the study are first author Jin-Sung Chung, Ph.D., Instructor of Dermatology; Ponciano Cruz Jr., M.D., Professor of Dermatology; Hans Hammers, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; and Lei Guo, Ph.D., Computational Biologist in the Quantitative Biomedical Research Center in the O’Donnell School of Public Health.
Dr. Xu is also a member of the Simmons Cancer Center.
The research was supported by the Department of Defense Kidney Cancer Research Program (W81XWH-20-1-0905), a VA Merit Award (1 I01 BX004069-01), and a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.