AbstractFumarate hydratase (FH) mutated papillary renal cell carcinoma is an aggressive variant of kidney cancer that poorly responds to conventional targeted therapies and immunotherapy. Here, we present the 10-year follow-up of a heavily pre-treated patient with several lines of therapy, achieving a remarkable complete response to anti-PD-1 rechallenge.

摘要富马酸水合酶（FH）突变的乳头状肾细胞癌是肾癌的一种侵袭性变体，对常规靶向治疗和免疫治疗反应不佳。在这里，我们介绍了一名经过多次治疗的患者的10年随访，该患者接受了多种治疗，对抗PD-1再次攻击取得了显着的完全反应。

In addition, we highlight a common immune-related adverse event of anti-PD-1, eosinophilia, as a possible biomarker of response and using TCGA data analysis, provide proof-of-concept for tumor expression of the eosinophil-related gene SIGLEC8, as a promising powerful predictor of prognosis for papillary renal cell carcinoma patients..

此外，我们强调了抗PD-1，嗜酸性粒细胞增多的常见免疫相关不良事件，作为反应的可能生物标志物，并使用TCGA数据分析，为嗜酸性粒细胞相关基因SIGLEC8的肿瘤表达提供了概念证明，作为乳头状肾细胞癌患者预后的有力预测指标。。

IntroductionFumarate hydratase (FH) mutated papillary renal cell carcinoma (pRCC), formerly known as type 21, is a rare and aggressive form of kidney cancer often linked with hereditary leiomyomatosis (HLRCC) syndrome2. This variant arises from inactivating mutations in the FH gene, leading to the accumulation of fumarate, which disrupts cellular metabolism and promotes tumorigenesis2,3,4.

简介富马酸水合酶（FH）突变的乳头状肾细胞癌（pRCC），以前称为21型，是一种罕见的侵袭性肾癌，常与遗传性平滑肌瘤病（HLRCC）综合征相关2。这种变异是由FH基因的失活突变引起的，导致富马酸盐的积累，从而破坏细胞代谢并促进肿瘤发生2,3,4。

The FH-deficient pRCC generally has a poor prognosis, with most patients presenting at advanced stages and having shorter 5-year survival than other types of pRCC due to rapid progression and metastasis5,6. As the FH mutation triggers the upregulation of pro-angiogenic growth factors, vascular growth factor inhibitors (VEGFi; bevacizumab), tyrosine kinase inhibitors (TKI; sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), mammalian target of rapamycin inhibitors (mTORi; everolimus and temsirolimus) and endothelium growth inhibitors (EGFRi; erlotinib) have been used alone and more recently in combination with immune checkpoint inhibitors (ICI; ipilimumab, nivolumab, pembrolizumab, atezolimumab, and durvalumab)7,8,9.FH-mutated pRCC cells preferably carry out aerobic glycolysis, decreasing glucose and increasing lactate, leading immune cells in the microenvironment to anergy and immunosuppression10,11.

FH缺陷型pRCC通常预后较差，大多数患者处于晚期，由于快速进展和转移，其5年生存期比其他类型的pRCC短5,6。由于FH突变触发促血管生成生长因子的上调，血管生长因子抑制剂（VEGFi；贝伐单抗），酪氨酸激酶抑制剂（TKI；舒尼替尼，索拉非尼，帕唑帕尼，阿西替尼和卡博替尼），哺乳动物雷帕霉素抑制剂靶点（mTORi；依维莫司和替西罗莫司）和内皮生长抑制剂（EGFRi；厄洛替尼）已被单独使用，最近与免疫检查点抑制剂（ICI；ipilimumab，nivolumab，pembrolizumab，atezolimumab和durvalumab）7,8,9.FH突变的pRCC细胞优选进行有氧糖酵解，降低葡萄糖和增加乳酸，导致微环境中的免疫细胞无能和免疫抑制10,11。

Glucose deprivation represses calcium signaling, IFN-γ production, cytotoxicity, and motility in T cells; nevertheless, ICI re-energizes anabolic metabolism and glycolysis in exhausted T cells12. The standard of care for FH-mutated pRCC is still controversial and remains ultimately the physician’s recommendation13.

葡萄糖剥夺抑制T细胞中的钙信号传导，IFN-γ产生，细胞毒性和运动性；然而，ICI重新激活了耗尽的T细胞中的合成代谢和糖酵解12。FH突变pRCC的护理标准仍然存在争议，最终仍然是医生的建议13。

Based on the European Society for Medical Oncology (ESMO) guidelines, monotherapy TKI with cabozantinib (over sunitinib) and pembrolizumab are currently considered st.

根据欧洲肿瘤内科学会（ESMO）指南，目前认为使用卡博替尼（优于舒尼替尼）和派姆单抗的单一疗法TKI是st。

High serum lactate dehydrogenase (LDH) and neutrophil-to-lymphocyte ratio (NLR) have been associated with worse overall survival in cancer patients from different etiologies treated with immune checkpoint inhibitors (ICI), frequently used as biomarkers to predict outcomes and immune-related adverse events (irAEs)34,35,36.

高血清乳酸脱氢酶（LDH）和中性粒细胞与淋巴细胞比率（NLR）与免疫检查点抑制剂（ICI）治疗的不同病因的癌症患者的总体生存率较差有关，ICI常被用作预测结果和免疫相关不良事件（IRAE）34,35,36。

Here, neither showed any predictive trend before, during, or after nivolumab treatment (Fig. 3C, D). In contrast, only blood eosinophil frequency and absolute counts dramatically increased after nivolumab reestablishment and were sustained during complete response (Fig. 3B and Supplementary Fig. 1).

在这里，在nivolumab治疗之前，期间或之后都没有显示任何预测趋势（图3C，D）。相反，在nivolumab重建后，只有血液嗜酸性粒细胞频率和绝对计数显着增加，并且在完全反应期间持续存在（图3B和补充图1）。

Mechanistically, immunotherapy stimulates the production of IL-5 and IL-33 by CD4+ T cells, which induces the production of eosinophils in the bone marrow, increased systemic eosinophil circulation, and accumulation in the tumor site. Using an eosinophil gene signature (SIGLEC8, RNASE2, RNASE3, IL5RA, and CCR3), it was found that eosinophil infiltration inside the tumor correlates with increased CD8+ T cell and IFN-γ signatures and was shown that tumor eosinophils enhance CD8+ T cell activation, leading to tumor eradication37.

从机制上讲，免疫疗法刺激CD4+T细胞产生IL-5和IL-33，从而诱导骨髓中嗜酸性粒细胞的产生，增加全身嗜酸性粒细胞循环，并在肿瘤部位积聚。使用嗜酸性粒细胞基因标记（SIGLEC8，RNASE2，RNASE3，IL5RA和CCR3），发现肿瘤内嗜酸性粒细胞浸润与CD8+T细胞和IFN-γ标记增加相关，并显示肿瘤嗜酸性粒细胞增强CD8+T细胞活化，导致肿瘤根除37。

As an isolated fact, during the patient’s investigation of eosinophilia, CD8+ T cells were found to predominate amongst other lymphocytes in the bone marrow aspirate. A preliminary analysis of the TCGA Kidney Papillary Cell Carcinoma (type 2) dataset showed that high SIGLEC8 expression in tumors alone leads to increased overall survival (p = 0.002901, Fig.

作为一个孤立的事实，在患者对嗜酸性粒细胞增多的调查中，发现CD8+T细胞在骨髓抽吸物中的其他淋巴细胞中占主导地位。TCGA肾乳头状细胞癌（2型）数据集的初步分析显示，单独肿瘤中的高SIGLEC8表达导致总生存率增加（p＝0.002901，图）。

4A), disease-specific survival (p = 0.001500, Fig. 4B) and progression-free interval (p = 0.00009585, Fig. 4C). Except for the progression-free interval using IL5RA (p = 0.01690, Supplementary Fig. 2D), the eosinophil gene signature37 or any of its individual genes did not present a.

4A），疾病特异性生存（p=0.001500，图4B）和无进展间隔（p=0.00009585，图4C）。除了使用IL5RA的无进展间隔（p=0.01690，补充图2D）外，嗜酸性粒细胞基因特征37或其任何单个基因均不存在。

Data availability

数据可用性

The datasets used during the current study are available from the corresponding author upon reasonable request or included as Supplementary Data.

本研究中使用的数据集可根据合理要求从通讯作者处获得，或作为补充数据包括在内。

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Download referencesAcknowledgementsThis work was supported by grants to MACS from The Sao Paulo Research Foundation, FAPESP (11/05331-0, 12/23478-0, 14/10290-9 and 17-13868-9). We are grateful to Dr. Francisco J. Solano, Larissa Guilherme de Lucena, the Editor, and the Reviewers for their valuable insights and suggestions that contributed to the completion of this manuscript.

下载参考文献致谢这项工作得到了圣保罗研究基金会FAPESP（11/05331-0、12/23478-0、14/10290-9和17-13868-9）对MACS的资助。我们感谢Francisco J.Solano博士，编辑Larissa Guilherme de Lucena和审稿人的宝贵见解和建议，这些见解和建议有助于完成本手稿。

Dr. Ramaprasad Srinivasan, Dr. José Alexandre Marzagão Barbuto and Dr. Carlos Alberto Vargas Baéz provided clinical care to the patient. This work is dedicated to the patient and his family.FundingOpen access funding provided by the National Institutes of Health.Author informationAuthor notesIsabella PortugalPresent address: Department of Medicine, Cambridge Health Alliance, Cambridge, MA, USAMaria A.

Ramaprasad Srinivasan博士，JoséAlexandre Marzago Barbuto博士和Carlos Alberto Vargas Baéz博士为患者提供了临床护理。这项工作致力于患者及其家人。基金由国立卫生研究院提供的开放获取资金。作者信息作者注释Sisabella PortugalPresent地址：美国马萨诸塞州剑桥市剑桥健康联盟医学系。

Clavijo-SalomonPresent address: Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USAAuthors and AffiliationsCiências Médicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, BrazilIsabella PortugalCentro de Investigação Translacional em Oncologia (CTO), Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, BrazilIsabella Portugal & Maria A.

Clavijo-SalomonPresent地址：美国国立癌症研究所癌症研究中心癌症综合免疫学实验室，美国国立卫生研究院，贝塞斯达，医学博士作者和附属机构Cincias Médicas，圣保罗大学医学院（FMUSP），巴西圣保罗Isabella PortugalCentro de Investigação Translational em Oncologia巴西，保罗Isabella Portugal&Maria A。

Clavijo-SalomonDepartamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, BrazilMaria A. Clavijo-SalomonAuthorsIsabella PortugalView author publicationsYou can also search for this author in.

Clavijo Salomon巴西圣保罗大学生物科学研究所信息学系Maria A.Clavijo Solomon作者Isabella Portugal查看作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarMaria A. Clavijo-SalomonView author publicationsYou can also search for this author in

PubMed Google ScholarMaria A.Clavijo SalomonView作者出版物您也可以在

PubMed Google ScholarContributionsI.P. and M.A.C.S. collected, assembled, analyzed, and interpreted all the data regarding the patient. M.A.C.S. collected, analyzed and interpreted all the data regarding tumor expression analysis of SIGLEC8. I.P. and M.A.C.S. wrote and approved the final manuscript.

PubMed谷歌学术贡献。P、 和M.A.C.S.收集，组装，分析和解释了有关患者的所有数据。M、 A.C.S.收集，分析和解释了有关SIGLEC8肿瘤表达分析的所有数据。一、 P.和M.A.C.S.撰写并批准了最终稿件。

M.A.C.S. is accountable for all aspects of the work.Corresponding authorCorrespondence to.

M、 A.C.S.对工作的各个方面负责。相应的作者。

Maria A. Clavijo-Salomon.Ethics declarations

Maria A.Clavijo Salomon。道德宣言

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Reprints and permissionsAbout this articleCite this articlePortugal, I., Clavijo-Salomon, M.A. Complete response to fifth-line anti-PD-1 rechallenge in fumarate hydratase-mutated papillary renal cell carcinoma.

转载和许可本文引用本文葡萄牙，I.，Clavijo Salomon，M.A。对富马酸水合酶突变的乳头状肾细胞癌中第五行抗PD-1再次攻击的完全反应。

npj Precis. Onc. 8, 251 (2024). https://doi.org/10.1038/s41698-024-00750-3Download citationReceived: 25 June 2024Accepted: 28 October 2024Published: 04 November 2024DOI: https://doi.org/10.1038/s41698-024-00750-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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