Adrenal metastasis in nivolumab‐treated renal cell carcinoma: A unique entity as a sanctuary site
Adrenal metastasis in nivolumab‐treated renal cell carcinoma: A unique entity as a sanctuary site
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DOI：
10.1111/iju.14833
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发表时间：
2022-02
影响因子：
2.6
通讯作者：
Yu Nakamura;S. Taguchi;M. Kinjo;M. Tambo;T. Okegawa;H. Fukuhara
中科院分区：
文献类型：
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作者：
Yu Nakamura;S. Taguchi;M. Kinjo;M. Tambo;T. Okegawa;H. Fukuhara
DOI: 10.1111 / iju.14833肾上腺是肾细胞癌相对常见的转移部位；大约6%接受根治性肾切除术合并肾上腺切除术的患者和29%的尸检病例有AM。包括纳武单抗在内的ICIs和tki是晚期RCC全身治疗的主要药物。在日本，自2016年以来，纳武单抗一直是首选的二线方案，自2018年以来，纳武单抗和伊匹单抗联合治疗一直是中/低风险患者的首选一线方案。最近的研究报道，肾上腺由于其特定的微环境可能是免疫治疗的“避难所”，AM可能对ICIs具有耐药性。然而，目前关于ICIs治疗RCC AM的研究还很缺乏。该研究得到了高丽大学医学院内部机构审查委员会的批准（批准号：1154）。我们回顾性回顾了2016年至2020年期间接受纳沃单抗单药治疗的47例晚期RCC患者，并确定了12例肾上腺受累患者（图1）。4例患者因以下原因被排除：开始纳沃单抗治疗前双侧肾上腺切除双侧AMs，合并晚期肝内胆管癌（AM原发部位不确定），同侧肾上腺直接侵袭RCC（转移距离RCC向肾上腺不远），以及纳沃单抗治疗结束后≥6个月AM发展。在剩下的8名患者中，4名在纳武单抗治疗开始前患有AM， 4名在接受纳武单抗治疗时发生AM。8例患者的详细临床资料汇总于表S1。在对纳武单抗治疗的反应中，所有8名患者最终表现出AM的进行性疾病，但从未出现萎缩；8例患者中有6例对其他内脏转移表现出疾病稳定和/或部分缓解（图1）。与之前的报道一致，我们的结果显示AM对nivolumab治疗晚期RCC有耐药性，尽管它对其他转移部位有效，这表明肾上腺是一个独特的避难所。很少有研究强调AM在各种癌症类型中对ICIs的反应方面的特殊性。Nguyen等人首先报道了3例AM进展（黑色素瘤，n = 2；子宫癌肉瘤，n = 1），尽管在其他转移部位有客观反应，但对派姆单抗的反应模式不同。Cohen等人报道了5例ci治疗的转移性结直肠癌患者，其疾病进展仅限于肾上腺。值得注意的是，他们证明了ici抵抗肾上腺病变中抗原递呈途径的显著损伤，这可以通过肾上腺微环境中内源性糖皮质激素的存在来解释。以前的研究报道，合成和内源性糖皮质激素都可以通过损害树突状细胞的抗原呈递或t细胞的激活来抑制抗癌免疫反应。Cohen等人也检测到TSC22D3过表达，TSC22D3是一种糖皮质激素靶基因，作为抗炎症和免疫抑制的中介。最后，Vaishampayan等人报道了12例RCC AM患者，其中包括5例使用不同方案的ICIs治疗的患者。尽管该队列的治疗概况不同，但与在其他转移部位实现的持久缓解相比，ICIs对AM无效；此外，TKIs和局部消融对AM有效。我们通过分析nivolumab单药治疗的晚期RCC同质队列，证明了AM对ICI治疗反应的特殊性，这为该主题提供了额外的见解。考虑到AM对ICIs的抵抗，局部治疗包括肾上腺切除术可能被考虑用于AM，特别是在孤立转移的情况下。然而，在RCC的情况下，TKIs也被认为对ici抗性AM有效。因此，应优化ICIs治疗RCC AM的治疗策略。在本研究中，3例患者（#4，#7和#8）可能是AM局部治疗的候选者，因为除了AM之外的所有转移都得到了控制，没有一例患者由于表现不佳和合并症而接受了局部治疗。同时，在纳武单抗后接受分子靶向治疗的5例患者中
DOI: 10.1111/iju.14833 The adrenal gland is a relatively common metastatic site of RCC; approximately 6% of patients undergoing radical nephrectomy with adrenalectomy and 29% of autopsy cases have AM. ICIs, including nivolumab, as well as TKIs are the mainstays of systemic therapy for advanced RCC. In Japan, nivolumab monotherapy has been a preferred second-line regimen since 2016 and combination therapy of nivolumab and ipilimumab has been a preferred firstline regimen for intermediate/poor-risk patients since 2018. Recent studies have reported that the adrenal gland may be a “sanctuary” site for immunotherapy due to its specific microenvironment and that AM is likely to be resistant to ICIs. However, studies on AM of RCC treated with ICIs are lacking. This study was approved by the internal Institutional Review Board of Kyorin University School of Medicine (approval number: 1154). We retrospectively reviewed 47 patients with advanced RCC who were treated with nivolumab monotherapy between 2016 and 2020 and identified 12 patients with adrenal involvement (Fig. 1). Four patients were excluded because of the following reasons: bilateral adrenalectomy for bilateral AMs before initiation of nivolumab therapy, concomitant advanced intrahepatic cholangiocarcinoma (uncertain primary site of AM), direct invasion of RCC in the ipsilateral adrenal gland (the metastasis was not distant from the RCC to the adrenal gland), and development of AM ≥6 months after the end of nivolumab therapy. Of the remaining eight patients, four had AM before the start of nivolumab therapy and four developed AM while receiving nivolumab therapy. The detailed clinical information of the eight patients is summarized in Table S1. In response to nivolumab therapy, all eight patients eventually exhibited progressive disease for AM without ever experiencing shrinkage; six of the eight patients showed stable disease and/or partial response for other visceral metastases (Fig. 1). Consistent with previous reports, our results showed that AM is resistant to nivolumab therapy for advanced RCC despite its efficacy at other metastatic sites, suggesting that the adrenal gland is a unique entity as a sanctuary site. Few studies have highlighted the particularity of AM in terms of its response to ICIs in miscellaneous cancer types. Nguyen et al. first reported three cases (melanoma, n = 2; uterine carcinosarcoma, n = 1) of AM progression with heterogeneous patterns of response to pembrolizumab despite an objective response at other metastatic sites. Cohen et al. reported five patients with ICI-treated metastatic colorectal cancer with disease progression limited to the adrenal glands. Notably, they demonstrated significant impairment of the antigen presentation pathway in the ICI-resistant adrenal lesion, which could be explained by the presence of endogenous glucocorticoids in the adrenal gland microenvironment. Previous studies reported that both synthetic and endogenous glucocorticoids could inhibit anticancer immune response through an impairment of the antigen presentation by dendritic cells or the activation of T-cells. Cohen et al. also detected overexpression of TSC22D3, which is a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. Finally, Vaishampayan et al. reported 12 patients with AM of RCC, including five cases treated with ICIs of various regimens. Despite the heterogeneous treatment profiles of the cohort, ICIs were ineffective against AM in comparison with durable remission achieved at other metastatic sites; furthermore, TKIs and local ablation were effective for AM. We demonstrated the particularity of AM in its response to ICI therapy by analyzing a homogeneous cohort of advanced RCC treated with nivolumab monotherapy, which provides additional insight into this topic. Given the resistance of AM to ICIs, focal therapy including adrenalectomy may be considered for AM, particularly in the case of solitary metastasis. In the case of RCC, however, TKIs are also considered effective for ICI-resistant AM. The treatment strategy for AM of RCC treated with ICIs should therefore be optimized. In this study, three patients (#4, #7, and #8) might be candidates for local therapy of AM because all metastases other than AM were controlled, none of whom underwent it due to poor performance status and comorbidities. Meanwhile, of five patients who received molecular-targeted therapy after nivolumab