系统纵向免疫分析将增殖的Treg细胞确定为免疫治疗益处的预测因素：来自3期CONTINUUM和DIPPER试验的生物标志物分析-动脉网

Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials

Nature 等信源发布 2024-10-23 07:39

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AbstractThe identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma.

摘要在许多研究中，由于缺乏对照组，免疫治疗预测因子的鉴定往往受到阻碍，因此很难区分预后和预测性生物标志物。这项研究提出了来自3期连续试验（NCT03700476）的生物标志物分析，这是第一个表明在放化疗（CRT）中加入抗PD-1（aPD1）可改善局部晚期鼻咽癌患者的无事件生存期（EFS）。

A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome.

使用质谱仪对来自aPD1 CRT组中12对匹配的复发和非复发患者的外周血单核细胞样品进行动态单细胞图谱分析。使用监督表示学习算法，我们鉴定了表达高水平活化和免疫抑制分子（包括FOXP3，CD38，HLA-DR，CD39和PD-1）的Ki67+增殖调节性T细胞（Tregs）群体，其丰度与治疗结果相关。

The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs.

与非复发者相比，复发患者的这些Ki67+Tregs频率在基线时显着更高，并且在治疗期间增加。通过流式细胞术进一步验证（n=120）证实了该Treg子集的预测价值。多重免疫组织化学（n=249）表明，肿瘤中的Ki67+Tregs可以预测免疫治疗的益处，aPD1仅在Ki67+Tregs基线水平低的患者中改善EFS。

These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies..

这些发现在多中心3期DIPPER试验（n=262，NCT03427827）和非小细胞肺癌抗PD-L1免疫治疗的3期OAK试验中得到了进一步验证，强调了Ki67+Treg频率在确定免疫治疗受益人和潜在指导个性化治疗策略方面的预测价值。。

IntroductionThe advent of immune checkpoint inhibitors (ICI) has transformed cancer treatment over the past decade. However, the limited response rate of 20–30% among patients with solid tumors, coupled with the potential for immunotherapy-related toxicities and the relatively high cost, underscores the critical need for optimal patient selection.

引言免疫检查点抑制剂（ICI）的出现在过去十年中改变了癌症治疗。然而，实体瘤患者的有限反应率为20-30%，加上免疫治疗相关毒性的可能性和相对较高的成本，强调了对最佳患者选择的迫切需求。

In this context, numerous biomarkers for ICI treatment have been reported. However, only a few of them have been validated in a randomized setting and implemented in clinical practice, such as programmed cell death 1 ligand 1(PD-L1) expression, tumor mutation burden (TMB), and microsatellite instability.1,2 The predictive value of these biomarkers is not consistent across different types of cancer, indicating that other biological factors determining the efficacy of ICI remain undiscovered.

。然而，其中只有少数已经在随机环境中得到验证并在临床实践中实施，例如程序性细胞死亡1配体1（PD-L1）表达，肿瘤突变负荷（TMB）和微卫星不稳定性[1,2]。这些生物标志物的预测价值在不同类型的癌症中并不一致，表明决定ICI疗效的其他生物学因素仍未被发现。

For example, while PD-L1 expression has been considered a predictive biomarker in several cancers, recent studies have shown that patients with nasopharyngeal carcinoma (NPC) can benefit from anti-PD-1 immunotherapy regardless of PD-L1 expression.3,4,5 Additionally, few genetic mutations are identified in NPC, indicating that TMB is not a useful predictor in this setting.6 These results highlight the unmet need for novel predictive markers for immunotherapy.Peripheral blood mononuclear cell (PBMC) samples are ideal sources for biomarker development due to their minimally invasive nature and clinical feasibility for dynamically monitoring tumor evolution and therapy responses.

例如，虽然PD-L1表达被认为是几种癌症的预测性生物标志物，但最近的研究表明，无论PD-L1表达如何，鼻咽癌（NPC）患者都可以从抗PD-1免疫治疗中受益[3,4,5]。此外，在NPC中几乎没有发现基因突变，表明TMB在这种情况下不是一个有用的预测因子[6]。这些结果突显了对新型免疫治疗预测标志物的需求尚未得到满足。外周血单核细胞（PBMC）样品由于其微创性质和动态监测肿瘤进展和治疗反应的临床可行性，是生物标志物开发的理想来源。

Although the immune cell composition in peripheral blood is different from that in the tumor microenvironment (TME), previous studies have shown that not only the immune subsets identified in the periphery could be detected in the TME, but also the expression of some m.

尽管外周血中的免疫细胞组成与肿瘤微环境（TME）中的免疫细胞组成不同，但先前的研究表明，不仅可以在TME中检测到在外周中鉴定出的免疫亚群，还可以检测到一些m的表达。

Data availability

数据可用性

Publicly available bulk RNA-seq and scRNA-seq datasets analyzed in this study were retrieved from the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/geo/) with the accession numbers GSE91061, GSE200996, and GSE162025. Bulk RNA-seq data of the phase 3 randomized OAK trial were retrieved from the European Genome-phenome Archive (EGAS00001005013).

本研究中分析的公开可用的批量RNA-seq和scRNA-seq数据集是从Gene Expression Omnibus（GEO）数据库（www.ncbi.nlm.nih.gov/GEO/）中检索的，登录号为GSE91061，GSE200996和GSE162025。从欧洲基因组-现象组档案（EGAS0001005013）中检索了3期随机OAK试验的大量RNA-seq数据。

All the key raw research data were uploaded onto the Research Data Deposit public platform (www.researchdata.org.cn) with the approval number RDDB2024118962, and could be obtained upon reasonable request. Source data are provided with this paper..

所有关键的原始研究数据都上传到了研究数据存储公共平台（www.researchdata.org.cn），批准号为RDDB2024118962，可以在合理的要求下获得。本文提供了源数据。。

ReferencesPowles, T. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat. Med. 25, 1706–1714 (2019).Article

参考文献Powles，T。等人。ABACUS试验中新辅助阿唑珠单抗治疗可手术尿路上皮癌的临床疗效和生物标志物分析。《自然医学杂志》251706-1714（2019）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).Article

Cristescu，R。等人。基于PD-1检查点阻断的免疫疗法的泛肿瘤基因组生物标志物。科学362，eaar3593（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yang, Y. et al. Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: a multicenter phase 3 trial (RATIONALE-309). Cancer Cell 41, 1061–1072.e4 (2023).Article

Yang，Y.等。Tislelizumab联合化疗作为复发或转移性鼻咽癌的一线治疗：一项多中心3期临床试验（Rational-309）。癌细胞411061-1072.e4（2023）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Mai, H. Q. et al. Toripalimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: the JUPITER-02 randomized clinical trial. JAMA 330, 1961–1970 (2023).Article

Mai，H。Q。等人。托利帕利单抗联合化疗治疗复发或转移性鼻咽癌：JUPITER-02随机临床试验。JAMA 3301961-1970（2023）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Chan, A. T. C. et al. Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 34, 251–261 (2023).Article

Chan，A.T.C.等人，《Pembrolizumab单药治疗与铂类药物预处理、复发或转移性鼻咽癌化疗的对比研究》（KEYNOTE-122）：一项开放标签、随机、III期临床试验。安科。Off.J.Eur.Soc.Med.Oncol。34251-261（2023）。文章

CAS

中科院

Google Scholar

谷歌学者

Wang, F. H. et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 39, 704–712 (2021).Article

Wang，F.H.等人。托利帕利单抗在先前治疗的复发或转移性鼻咽癌中的疗效，安全性和相关生物标志物：II期临床试验（POLARIS-02）。J、临床。Oncol公司。关闭J.Am.Soc.Clin。Oncol公司。39704-712（2021）。文章

CAS

中科院

Google Scholar

谷歌学者

Cader, F. Z. et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat. Med. 26, 1468–1479 (2020).Article

Cader，F.Z.等人。经典霍奇金淋巴瘤患者对PD-1阻断反应的外周免疫特征。《自然医学》261468-1479（2020）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Steele, N. G. et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat. Cancer 1, 1097–1112 (2020).Article

Steele，N.G.等人。人类胰腺癌中肿瘤和外周血免疫景观的多模式映射。《自然癌症》11097-1112（2020）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Gadalla, R. et al. Validation of CyTOF against flow cytometry for immunological studies and monitoring of human cancer clinical trials. Front. Oncol. 9, 415 (2019).Article

Gadalla，R。等人。验证CyTOF对流式细胞术的免疫研究和人类癌症临床试验监测。正面。Oncol公司。9415（2019）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, X. et al. Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. Lancet 403, 2720–2731 (2024).Ma, J.

Liu，X。等。中国局部晚期鼻咽癌患者使用或不使用辛迪单抗诱导同步放化疗（CONTINUUM）：一项多中心，开放标签，平行组，随机，对照，3期临床试验。柳叶刀4032720-2731（2024）。马，J。

et al. Adjuvant PD-1 blockade with camrelizumab in high-risk locoregionally advanced nasopharyngeal carcinoma (DIPPER): a multicenter, open-label, phase 3, randomized controlled trial. J. Clin. Oncol. 42, LBA6000–LBA6000 (2024).Article .

camrelizumab辅助PD-1阻断治疗高危局部晚期鼻咽癌（DIPPER）：一项多中心、开放标签、3期随机对照试验。J、临床。Oncol公司。42，LBA6000–LBA6000（2024）。文章。

Google Scholar

谷歌学者

Van Gassen, S. et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytom. A 87, 636–645 (2015).Article

Van Gassen，S。等人。FlowSOM：使用自组织图可视化和解释细胞计数数据。Cytom公司。A 87636-645（2015）。文章

Google Scholar

谷歌学者

Li, X. M. et al. The immune modulation effects of gemcitabine plus cisplatin induction chemotherapy in nasopharyngeal carcinoma. Cancer Med. 11, 3437–3444 (2022).Article

Li，X.M.等。吉西他滨联合顺铂诱导化疗对鼻咽癌的免疫调节作用。癌症医学113437-3444（2022）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Heylmann, D., Rodel, F., Kindler, T. & Kaina, B. Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim. Biophys. Acta 1846, 121–129 (2014).PubMed

Heylmann，D.，Rodel，F.，Kindler，T。＆Kaina，B。人和鼠外周血淋巴细胞，干细胞和祖细胞的辐射敏感性。生物化学。生物物理。Acta 1846121–129（2014）。PubMed出版社

CAS

中科院

Google Scholar

谷歌学者

Muroyama, Y. & Wherry, E. J. Memory T-cell heterogeneity and terminology. Cold Spring Harb. Perspect. Biol. 13, a037929 (2021).Zhang, Q. et al. Mass cytometry-based peripheral blood analysis as a novel tool for early detection of solid tumours: a multicentre study. Gut 72, 996–1006 (2023).Article .

Muroyama，Y。＆Wherry，E.J。记忆T细胞异质性和术语。冷泉兔。透视图。生物学13，a037929（2021）。Zhang，Q.等人。基于大规模细胞计数的外周血分析作为早期检测实体瘤的新工具：一项多中心研究。肠道72996-1006（2023）。文章。

PubMed

CAS

中科院

Google Scholar

谷歌学者

Arvaniti, E. & Claassen, M. Sensitive detection of rare disease-associated cell subsets via representation learning. Nat. Commun. 8, 14825 (2017).Article

Arvaniti，E。＆Claassen，M。通过表征学习敏感检测罕见疾病相关细胞亚群。国家公社。814825（2017）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).Article

Miyara，M。等人。表达FoxP3转录因子的人CD4+T细胞的功能描绘和分化动力学。豁免30899–911（2009）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Luoma, A. M. et al. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185, 2918–2935.e2929 (2022).Article

Luoma，A.M.等人。组织驻留记忆和循环T细胞是术前癌症免疫治疗的早期反应者。细胞1852918–2935.e2929（2022）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Savage, P. A., Klawon, D. E. J. & Miller, C. H. Regulatory T cell development. Annu. Rev. Immunol. 38, 421–453 (2020).Article

Savage，P.A.，Klawon，D.E.J。和Miller，C.H。调节性T细胞发育。年。修订版Immunol。38421-453（2020）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Yin, X., Chen, S. & Eisenbarth, S. C. Dendritic cell regulation of T helper cells. Annu. Rev. Immunol. 39, 759–790 (2021).Article

Yin，X.，Chen，S。＆Eisenbarth，S.C。树突状细胞调节T辅助细胞。年。修订版Immunol。39759-790（2021）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Kim, C. G. et al. A phase II open-label randomized clinical trial of preoperative durvalumab or durvalumab plus tremelimumab in resectable head and neck squamous cell carcinoma. Clin. Cancer Res. 30, 2097–2110 (2024).Article

Kim，C.G.等人，术前durvalumab或durvalumab加tremelimumab治疗可切除头颈部鳞状细胞癌的II期开放标签随机临床试验。临床。癌症研究302097-2110（2024）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Feng, X. et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma. Clin. Cancer Res. 23, 4290–4300 (2017).Article

Feng，X。等人。靶向CD38抑制T调节细胞的诱导和功能，以减轻多发性骨髓瘤的免疫抑制。临床。癌症研究234290-4300（2017）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Ma, X. et al. Human HLA-DR+CD27+ regulatory T cells show enhanced antigen-specific suppressive function. JCI Insight 8, e162978 (2023).Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat.

Ma，X。等人。人类HLA-DR+CD27+调节性T细胞显示出增强的抗原特异性抑制功能。JCI Insight 8，e162978（2023）。Kumagai，S。等人。效应T细胞和调节性T细胞之间的PD-1表达平衡预测了PD-1阻断疗法的临床疗效。纳特。

Immunol. 21, 1346–1358 (2020).Article .

免疫。211346-1358（2020）。文章。

PubMed

CAS

中科院

Google Scholar

谷歌学者

Tay, C., Tanaka, A. & Sakaguchi, S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell 41, 450–465 (2023).Article

Tay，C.，Tanaka，A。＆Sakaguchi，S。肿瘤浸润调节性T细胞作为癌症免疫治疗的靶标。癌细胞41450-465（2023）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Liu, Y. et al. Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. Nat. Commun. 12, 741 (2021).Article

Liu，Y。等。单细胞分辨率下鼻咽癌的肿瘤异质性和细胞间网络。国家公社。12741（2021）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).Article

。科学374，abe6474（2021）。文章

PubMed

Google Scholar

谷歌学者

Spasevska, I. et al. Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma. Blood Adv. 7, 7216–7230 (2023).Article

Spasevska，I。等。B细胞非霍奇金淋巴瘤中肿瘤内调节性T细胞的多样性。血液杂志77216-7230（2023）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Rossetti, M. et al. TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis. Ann. Rheum. Dis. 76, 435–441 (2017).Article

Rossetti，M。等人，TCR库测序鉴定了人类关节炎活动性炎症期间血流中的滑膜Treg细胞克隆型。安。瑞姆。Dis。。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Kamada, T. et al. PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl. Acad. Sci. USA 116, 9999–10008 (2019).Article

Kamada，T。等人。通过PD-1阻断扩增的PD-1（+）调节性T细胞促进癌症的过度进展。程序。纳特尔。阿卡德。科学。美国1169999–10008（2019）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Lindqvist, C. A. et al. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies. Immunology 131, 371–376 (2010).Article

Lindqvist，C.A。等人，T调节细胞部分通过B细胞恶性肿瘤患者可溶性CD25的释放来控制T细胞增殖。免疫学131371-376（2010）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Patil, N. S. et al. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer Cell 40, 289–300.e284 (2022).Article

Patil，N.S.等人肿瘤内浆细胞预测非小细胞肺癌PD-L1阻断的结果。癌细胞40289-300.e284（2022）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e916 (2017).Article

Riaz，N。等人。nivolumab免疫治疗期间的肿瘤和微环境演变。细胞171934-949.e916（2017）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Yip, W. K., Abdullah, M. A., Yusoff, S. M. & Seow, H. F. Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced zeta-chain expression in nasopharyngeal carcinoma patients. Clin. Exp. Immunol. 155, 412–422 (2009).Article

Yip，W.K.，Abdullah，M.A.，Yusoff，S.M。＆Seow，H.F。鼻咽癌患者中具有调节性T细胞免疫表型的肿瘤浸润淋巴细胞的增加和zeta链表达的降低。临床。实验免疫。155412-422（2009）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Lau, K. M. et al. Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients. Br. J. Cancer 96, 617–622 (2007).Article

。《癌症杂志》96617-622（2007）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Pedersen, C. B. et al. cyCombine allows for robust integration of single-cell cytometry datasets within and across technologies. Nat. Commun. 13, 1698 (2022).Article

Pedersen，C.B。等人的cyCombine允许在技术内部和技术之间对单细胞细胞计数数据集进行强大的集成。国家公社。131698（2022）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Nowicka, M. et al. CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets. F1000Res. 6, 748 (2017).Article

Nowicka，M。等人。CyTOF工作流程：高通量高维细胞计数数据集中的差异发现。F1000Res。6748（2017）。文章

PubMed

Google Scholar

谷歌学者

Iwata, Y. et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011).Article

Iwata，Y。等人。人类中罕见的IL-10感受态B细胞亚群的表征，其与小鼠调节性B10细胞平行。血液117530-541（2011）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Ziegler-Heitbrock, L. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 116, e74–e80 (2010).Article

Ziegler-Heitbrock，L.等人。血液中单核细胞和树突状细胞的命名法。血液116，e74-e80（2010）。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Freud, A. G., Mundy-Bosse, B. L., Yu, J. & Caligiuri, M. A. The broad spectrum of human natural killer cell diversity. Immunity 47, 820–833 (2017).Article

。免疫力47820-833（2017）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e3529 (2021).Article

Hao，Y.等人。多模式单细胞数据的综合分析。细胞1843573-3587.e3529（2021）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

McGinnis, C. S., Murrow, L. M. & Gartner, Z. J. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst. 8, 329–337.e324 (2019).Article

McGinnis，C.S.，Murrow，L.M。＆Gartner，Z.J。DoubletFinder：使用人工最近邻在单细胞RNA测序数据中进行双重检测。细胞系统。8329-337.e324（2019）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).Article

Trapnell，C。等人。通过单细胞的伪时间顺序揭示了细胞命运决定的动力学和调节因子。美国国家生物技术公司。32381-386（2014）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Chen, Y. P. et al. Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma. Cell Res. 30, 1024–1042 (2020).Article

Chen，Y.P.等。单细胞转录组学揭示了与鼻咽癌预后相关的免疫细胞多样性和免疫亚型的调节因子。Cell Res.301024-1042（2020）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Li, J. Y. et al. TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models. Nat. Commun. 14, 865 (2023).Article

Li，J。Y。等人TRIM21在鼻咽癌肿瘤模型中抑制辐射诱导的线粒体DNA释放并损害抗肿瘤免疫力。国家公社。14865（2023）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Liang, Y. L. et al. A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma. Nat. Commun. 13, 2996 (2022).Article

Liang，Y.L.等人。与肿瘤免疫异质性相关的lncRNA标记预测局部晚期鼻咽癌的远处转移。国家公社。132996（2022）。文章

PubMed

PubMed Central

公共医学中心

CAS

中科院

Google Scholar

谷歌学者

Qiao, H. et al. Association of intratumoral microbiota with prognosis in patients with nasopharyngeal carcinoma from 2 hospitals in China. JAMA Oncol. 8, 1301–1309 (2022).Article

Qiao，H。等。中国两家医院鼻咽癌患者肿瘤内微生物群与预后的关系。JAMA Oncol。81301-1309（2022）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 14, 7 (2013).Article

Hanzelmann，S.，Castelo，R。＆Guinney，J。GSVA：微阵列和RNA-seq数据的基因组变异分析。BMC生物信息。14，7（2013）。文章

Google Scholar

谷歌学者

Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).Article

Eisenhauer，E.A.等人，《实体瘤新的反应评估标准：修订的RECIST指南（1.1版）》。。文章

PubMed

CAS

中科院

Google Scholar

谷歌学者

Download referencesAcknowledgementsThis work was supported by grants from the National Natural Science Foundation of China (81930072, 82101750, 82172870, 82202943, 82373312, and 82403896), Natural Science Foundation of Guangdong Province (2024B1515020114), Science and Technology Plan Project of Guangzhou (2024A04J3943), Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0005), Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center (CKS-SYSUCC-2023004).

下载参考文献致谢这项工作得到了国家自然科学基金（81930072、82101750、82172870、82202943、82373312和82403896），广东省自然科学基金（2024B1515020114），广州市科技计划项目（2024A04J3943），中山大学癌症中心癌症创新研究计划（CIRP-SYSUCC-0005），中山大学癌症中心杰出青年医师Chih Kuang奖学金（CKS-SYSUCC-2023004）的资助。

We thank the staff of Core Facilities at State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center for technical support for CyTOF.Author informationAuthor notesThese authors contributed equally: Sai-Wei Huang, Wei Jiang, Sha Xu, Yuan Zhang, Juan DuAuthors and AffiliationsDepartment of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR ChinaSai-Wei Huang, Wei Jiang, Yuan Zhang, Juan Du, Ya-Qin Wang, Cheng Xu, Ying Sun, Jun Ma, Ye-Lin Liang & Xu LiuDepartment of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR ChinaSha Xu, Han Qiao & Na LiuCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR ChinaKun-Yu YangDepartment of Radiation Oncology, The Fi.

我们感谢中山眼科中心眼科国家重点实验室核心设施的工作人员为CyTOF提供的技术支持。作者信息作者注意到，这些作者做出了同样的贡献：黄赛伟，蒋伟，沙旭，张元，杜娟作者和附属机构放射肿瘤学系，华南肿瘤学国家重点实验室，癌症医学协同创新中心，广东省鼻咽癌诊断与治疗重点实验室，广东省癌症临床研究中心，中山大学肿瘤中心，广州，中国赛伟黄，蒋伟，张元，杜娟，王亚琴，程旭，孙英，马军，梁叶林，刘旭华南肿瘤学国家重点实验室，癌症医学协同创新中心，广东省鼻咽癌诊断与治疗重点实验室，广东省中山大学肿瘤中心肿瘤临床研究中心，广州，中华人民共和国徐莎，韩桥和刘娜肿瘤中心，同济医学院附属协和医院，华中科技大学放射肿瘤学系，武汉。

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PubMed Google ScholarContributionsConception and design: N.L., Y.S., J.M., Y.-L.L., X.L.; development of methodology: S.-W.H., W.J., S.X., Y.Z., Y.-L.L.; experiment implement: S.-W.H., W.J., S.X., Y.Z., J.D., Y.-L.L.; acquisition of sample and data: Y.-Q.W., K.-Y.Y., N.Z., F.L., G.-R.Z., F.J., H.-J.W., Y.-Y.Z., X.-D.Z., N.-Y.C.; analysis and interpretation of data: S.-W.H., W.J., S.X., Y.Z., J.D., Y.-L.L., C.X., H.Q.; writing the manuscript: S.-W.H., W.J., S.X., Y.Z., Y.-L.L.; revision of the manuscript: N.L., Y.S., J.M., X.L., Y.-Q.W., K.-Y.Y., N.Z., F.L., G.-R.Z., F.J., H.-J.W., Y.-Y.Z., X.-D.Z., N.-Y.C., C.X., H.Q.; administrative, technical, or material support: N.L., Y.S., J.M., X.L.; study supervision: N.L., Y.S., J.M., X.L.

PubMed谷歌学术贡献概念与设计：N.L.，Y.S.，J.M.，Y.-L.L.，X.L。；方法论的发展：S.-W.H.，W.J.，S.X.，Y.Z.，Y.-L.L。；实验实施：S.-W.H.，W.J.，S.X.，Y.Z.，J.D.，Y.-L.L。；样本和数据的获取：Y.-Q.W.，K.-Y.Y.，N.Z.，F.L.，G.-R.Z.，F.J.，H.-J.W.，Y.-Y.Z.，X.-D.Z.，N.-Y.C。；数据分析和解释：S.-W.H.，W.J.，S.X.，Y.Z.，J.D.，Y.-L.L.，C.X.，H.Q。；撰写手稿：S.-W.H.，W.J.，S.X.，Y.Z.，Y.-L.L。；手稿的修订：N.L.，Y.S.，J.M.，X.L.，Y.-Q.W.，K.-Y.Y.，N.Z.，F.L.，G.-R.Z.，F.J.，H.-J.W.，Y.-Y.Z.，X.-D.Z.，N.-Y.C.，C.X.，H.Q。；行政，技术或物质支持：N.L.，Y.S.，J.M.，X.L。；研究监督：N.L.，Y.S.，J.M.，X.L。

All authors reviewed and approved the final manuscript.Corresponding authorsCorrespondence to.

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Jun Ma, Ye-Lin Liang or Xu Liu.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleHuang, SW., Jiang, W., Xu, S. et al. Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials.

转载和许可本文引用本文Huang，SW。，Jiang，W.，Xu，S.等人。系统性纵向免疫分析将增殖的Treg细胞鉴定为免疫治疗益处的预测因子：来自3期连续体和DIPPER试验的生物标志物分析。

Sig Transduct Target Ther 9, 285 (2024). https://doi.org/10.1038/s41392-024-01988-wDownload citationReceived: 19 March 2024Revised: 09 September 2024Accepted: 24 September 2024Published: 23 October 2024DOI: https://doi.org/10.1038/s41392-024-01988-wShare 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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