肿瘤细胞治疗研究
英文原题：Papillary renal cell carcinoma with high-ABCC2 shows an immune-evasive profile associated with favorable response to immunotherapy.
Papillary renal cell carcinoma with high-ABCC2 shows an immune-evasive profile associated with favorable response to immunotherapy.
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ABCC2 高表达的 PRCC 是免疫浸润型肿瘤，具有抑制性表型，可能对免疫检查点抑制剂有反应。
免疫检查点抑制剂的使用是转移性乳头状肾细胞癌（PRCC）一种有前景的治疗策略；然而，预测性生物标志物仍然有限。ABCC2高表达的PRCC代表一个侵袭性亚群，常与转移相关。这些肿瘤的肿瘤微环境（TME）特征仍定义不清。本研究旨在根据ABCC2状态来刻画PRCC的TME特征。评估了一个发现队列，包括157例ABCC2高表达PRCC、156例ABCC2低表达PRCC和72例正常肾脏。利用RNA测序数据，评估了免疫细胞组成、免疫检查点标志物和免疫特征评分。在一个独立队列（31例ABCC2高表达、36例ABCC2低表达和15例正常肾脏）中使用RNA原位杂交（RNA-ISH）和免疫组织化学（IHC）进行了验证。与ABCC2低表达肿瘤相比，ABCC2高表达PRCC表现出细胞毒性T细胞（p < 0.001）、M2巨噬细胞（p = 0.021）和调节性T细胞（p < 0.001）浸润增加。ABCC2高表达PRCC还表现出免疫检查点生物标志物表达更高，包括程序性细胞死亡配体1（PD-L1）（p < 0.001）。验证队列显示了相似的TME特征。此外，ABCC2高表达PRCC具有更高的PD-L1 IHC阳性率（联合阳性评分 ≥ 1，p = 0.035；肿瘤比例评分 ≥ 1%，p = 0.006）和免疫预测特征评分（p = 0.029）。与ABCC2低表达PRCC相比，NRF2-抗氧化反应元件信号通路在ABCC2高表达PRCC中富集，表现为通路分析中的过度代表、更高的基因特征评分（p < 0.001）和升高的转录信号（NFE2L2，p < 0.001；NQO1，p < 0.001）。总之，ABCC2 高表达的 PRCC 是免疫细胞浸润的肿瘤，具有抑制性表型，可能对免疫检查点抑制剂有反应。ABCC2 IHC 可作为预测性生物标志物，有助于识别可能从此类治疗中获益的患者。© 2025 作者。The Journal of Pathology 由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。
The use of immune checkpoint inhibitors is a promising therapeutic strategy for metastatic papillary renal cell carcinoma (PRCC); however, predictive biomarkers remain limited. PRCCs with high ABCC2 expression represent an aggressive subset frequently associated with metastasis. The tumor microenvironment (TME) profile of these tumors remains poorly defined. This study aims to characterize the TME of PRCC in relation to its ABCC2 status. A discovery cohort of 157 ABCC2-high PRCCs, 156 ABCC2-low PRCCs, and 72 normal kidneys was evaluated. Using RNA sequencing data, immune cell composition, immune checkpoint markers, and immune signature scores were assessed. Validation was performed in an independent cohort (31 ABCC2-high, 36 ABCC2-low, and 15 normal kidneys) using RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC). ABCC2-high PRCCs demonstrated increased infiltration of cytotoxic T cells (p < 0.001), M2 macrophages (p = 0.021), and regulatory T cells (p < 0.001) compared to ABCC2-low tumors. ABCC2-high PRCCs also had higher expression of immune checkpoint biomarkers including programmed cell death ligand 1 (PD-L1) (p < 0.001). The validation cohort showed this similar TME profile. Additionally, ABCC2-high PRCCs had higher PD-L1 IHC positivity (combined positive score ≥ 1, p = 0.035; tumor proportion score ≥ 1%, p = 0.006) and immune predictive signature score (p = 0.029). NRF2-Antioxidant Response Element signaling pathway was enriched in ABCC2-high PRCCs as evidenced by overrepresentation in pathway analysis, higher gene signature score (p < 0.001), and elevated transcript signals (NFE2L2, p < 0.001; NQO1, p < 0.001), compared to ABCC2-low PRCCs. In conclusion, ABCC2-high PRCCs are immune-infiltrated tumors with a suppressive phenotype potentially responsive to immune checkpoint inhibitors. ABCC2 IHC may serve as a predictive biomarker to help identify patients likely to benefit from such therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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