Garige Mamatha, Poncet Sarah, Norris Alexis, Chou Chao-Kai, Wu Wells W, Shen Rong-Fong, Greenberg Jacob W, Krane Louis Spencer, Sourbier Carole
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.
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.
Life (Basel). 2023 May 17;13(5):1196. doi: 10.3390/life13051196.
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.
阿片类药物通常会长期开给晚期透明细胞肾细胞癌患者，以帮助进行疼痛管理。由于长期接触阿片类药物已被证明会影响血管系统并具有免疫抑制作用，我们研究了它如何影响透明细胞肾细胞癌的代谢和生理。对少量有长期阿片类药物接触或无阿片类药物接触的存档患者标本进行了RNA测序。使用CIBERSORT评估免疫浸润和微环境变化。在接触阿片类药物的肿瘤中观察到M1巨噬细胞和T细胞CD4记忆静止免疫亚群显著减少，而在其他免疫细胞中观察到的变化无统计学意义。进一步的RNA测序数据分析表明，未接触阿片类药物的标本和接触阿片类药物的标本之间KEGG信号通路的差异表达显著，基因特征从与有氧糖酵解一致转变为与三羧酸循环、烟酸代谢和cAMP信号通路一致。总之，这些数据表明长期接触阿片类药物会改变ccRCC的细胞代谢和免疫稳态，这可能会影响这些患者对治疗的反应，特别是如果治疗针对ccRCC肿瘤的微环境或代谢。
