Extended Opioid Exposure Modulates the Molecular Metabolism of Clear Cell Renal Cell Carcinoma
Mamatha Garige,
Sarah Poncet,
Alexis Norris,
Chao-Kai Chou,
Wells W. Wu,
Rong-Fong Shen,
Jacob W. Greenberg,
Louis Spencer Krane,
Carole Sourbier
Affiliations
Mamatha Garige
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Sarah Poncet
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Alexis Norris
Division of Animal Bioengineering and Cellular Therapies, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20852, USA
Chao-Kai Chou
Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Wells W. Wu
Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Rong-Fong Shen
Facility for Biotechnology Resources, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Jacob W. Greenberg
Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
Louis Spencer Krane
Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
Carole Sourbier
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Opioids are commonly prescribed for extended periods of time to patients with advanced clear cell renal cell carcinoma to assist with pain management. Because extended opioid exposure has been shown to affect the vasculature and to be immunosuppressive, we investigated how it may affect the metabolism and physiology of clear cell renal cell carcinoma. RNA sequencing of a limited number of archived patients’ specimens with extended opioid exposure or non-opioid exposure was performed. Immune infiltration and changes in the microenvironment were evaluated using CIBERSORT. A significant decrease in M1 macrophages and T cells CD4 memory resting immune subsets was observed in opioid-exposed tumors, whereas the changes observed in other immune cells were not statistically significant. Further RNA sequencing data analysis showed that differential expression of KEGG signaling pathways was significant between non-opioid-exposed specimens and opioid-exposed specimens, with a shift from a gene signature consistent with aerobic glycolysis to a gene signature consistent with the TCA cycle, nicotinate metabolism, and the cAMP signaling pathway. Together, these data suggest that extended opioid exposure changes the cellular metabolism and immune homeostasis of ccRCC, which might impact the response to therapy of these patients, especially if the therapy is targeting the microenvironment or metabolism of ccRCC tumors.
