リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「シングルセルトランスクリプトーム解析を用いた食道扁平上皮癌内の腫瘍浸潤Bリンパ球における化学療法後の機能変化の解明」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

シングルセルトランスクリプトーム解析を用いた食道扁平上皮癌内の腫瘍浸潤Bリンパ球における化学療法後の機能変化の解明

中村, 祥一 NAKAMURA, Shoichi ナカムラ, ショウイチ 九州大学

2023.09.25

概要

九州大学学術情報リポジトリ
Kyushu University Institutional Repository

Single-cell transcriptome analysis reveals
functional changes in tumour-infiltrating B
lymphocytes after chemotherapy in oesophageal
squamous cell carcinoma
中村, 祥一

https://hdl.handle.net/2324/7157298
出版情報:Kyushu University, 2023, 博士(医学), 課程博士
バージョン:
権利関係:Creative Commons Attribution 4.0 International

氏 名:

中村 祥一

論文名:

Single-cell transcriptome analysis reveals functional changes in tumourinfiltrating B lymphocytes after chemotherapy in oesophageal squamous cell
carcinoma
(シングルセルトランスクリプトーム解析を用いた食道扁平上皮癌内の腫瘍浸潤Bリ
ンパ球における化学療法後の機能変化の解明)

区 分:



論 文 内 容 の 要 旨

【背景と目的】腫瘍免疫微小環境は不均一性を有し、免疫療法の治療効果と関連している。食道癌は
予後不良な消化器癌の一種であるが、近年、免疫チェックポイント阻害薬と化学療法の併用療法の有
効性が示され、食道癌における化学療法に伴う腫瘍免疫微小環境の変化が注目されている。一般的
に、Bリンパ球は抗原刺激に伴い多様な分化サブタイプを呈しながら液性免疫の中心的役割を担ってい
る。一方で、腫瘍局所に存在するBリンパ球 (tumour-infiltrating B lymphocyte; TIL-B)は様々な癌
腫の良好な予後や免疫チェックポイント阻害薬の奏効率と相関していることが報告されているもの
の、その詳細な機能的役割は不明である。今回我々はTIL-Bの分化サブタイプの不均一性と化学療法に
伴う機能変動を詳細に評価するために食道癌及びリンパ節の切除標本を用いてシングルセルトランス
クリプトーム解析を行った。
【方法】食道扁平上皮癌10検体、食道正常粘膜部7検体、リンパ節6検体を含む計23検体を用いてシン
グルセルトランスクリプトーム解析を行った。また、抗体産生細胞の代表マーカーである抗IGKC抗体
を用いて、当科で切除術を行った食道扁平上皮癌166検体を対象に免疫組織化学染色を行い、無再発生
存期間や全生存期間との相関を評価した。
【結果】食道扁平上皮癌・正常粘膜部の計17検体を対象にシングルセル解析を行い、81,246細胞を同
定し24のクラスターに分類した。さらにBリンパ球クラスターのみを抜き出し、12の詳細な分化サブタ
イプを同定した。次に化学療法施行の有無に着目した検討では、Bリンパ球における共刺激因子関連遺
伝子やCD40シグナル関連遺伝子の発現が化学療法施行群で増強していた。ナイーブBリンパ球は化学療
法施行群でBリンパ球活性化関連遺伝子の発現が増強し全Bリンパ球に占める細胞数の割合が減少して
いた。また、化学療法施行群の抗体産生細胞は全Bリンパ球中に占める割合が増加し抗体産生能も増強
していたが、同時に遊走能が低下していた。食道癌のTCGAデータセットを用いて発現変動遺伝子と予
後との相関を評価したところ、抗体産生細胞における化学療法施行に伴う発現増強遺伝子群は食道癌
の無再発生存期間の延長と相関していた。一方、リンパ節を対象としたシングルセル解析では、転移
リンパ節においてBリンパ球の活性化は亢進し、抗体産生細胞の占める割合が増加していることが示さ
れ、原発巣と同様の結果であった。腫瘍局所の抗体産生細胞の臨床的意義を評価するために免疫組織
化学染色を行ったところ、IGKCの高発現は無再発生存期間・全生存期間の延長と有意に相関してお
り、多変量解析においても独立した予後良好因子であることが示された。
【結論】本研究結果はTIL-Bの詳細な分化サブタイプや化学療法に伴う機能的不均一性の変動について
新たな知見を提供し、消化器癌の腫瘍免疫微小環境に対するより詳細な理解につながるものと期待さ
れる。

この論文で使われている画像

参考文献

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020:

gLOBOCAN estimates of incidence and mortality worldwide for

36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

https://doi.org/10.3322/caac.21660

2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021.

CA Cancer J Clin. 2021;71(1):7-33. https://doi.org/10.3322/caac.

21654

3. Sun J-M, Shen L, Shah MA, et al. Pembrolizumab plus

chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a

randomised, placebo-controlled, phase 3 study. The Lancet.

2021;398(10302):759-771. https://doi.org/10.1016/s0140-6736(21)

01234-4

4. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571. https://doi.org/10.1038/

nature13954

5. Fucikova J, Kralikova P, Fialova A, et al. Human tumour

cells killed by anthracyclines induce a tumour-specific immune

response. Cancer Res. 2011;71(14):4821-4833. https://doi.org/10.

1158/0008-5472.CAN-11-0950

6. Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G.

The immune contexture in cancer prognosis and treatment.

Nat Rev Clin Oncol. 2017;14(12):717-734. https://doi.org/10.1038/

nrclinonc.2017.101

7. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer

immunotherapy: from T cell basic science to clinical practice.

Nat Rev Immunol. 2020;20(11):651-668. https://doi.org/10.1038/

s41577-020-0306-5

8. Berntsson J, Nodin B, Eberhard J, Micke P, Jirstrom K. Prognostic impact of tumour-infiltrating B cells and plasma cells in

colorectal cancer. Int J Cancer. 2016;139(5):1129-1139. https://doi.

org/10.1002/ijc.30138

9. Garnelo M, Tan A, Her Z, et al. Interaction between tumourinfiltrating B cells and T cells controls the progression of

hepatocellular carcinoma. Gut. 2017;66(2):342-351. https://doi.

org/10.1136/gutjnl-2015-310814

10. Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures

improve immunotherapy and survival in melanoma. Nature.

2020;577(7791):561-565. https://doi.org/10.1038/s41586-019-19148

11. Gilbert AE, Karagiannis P, Dodev T, et al. Monitoring the systemic human memory B cell compartment of

melanoma patients for anti-tumour IgG antibodies. PLoS One.

2011;6(4):e19330. https://doi.org/10.1371/journal.pone.0019330

12. Hladíková K, Koucký V, Bouček J, et al. Tumour-infiltrating

B cells affect the progression of oropharyngeal squamous cell

carcinoma via cell-to-cell interactions with CD8+ T cells.

J Immunother Cancer. 2019;7(1):261. https://doi.org/10.1186/

s40425-019-0726-6

13. Bruno TC, Ebner PJ, Moore BL, et al. Antigen-presenting intratumoural B cells affect CD4+ TIL phenotypes in non–small cell

lung cancer patients. Cancer Immunol Res. 2017;5(10):898-907.

https://doi.org/10.1158/2326-6066.cir-17-0075

14. Shi J-Y, Gao Q, Wang Z-C, et al. Margin-infiltrating CD20+

B cells display an atypical memory phenotype and correlate

with favorable prognosis in hepatocellular carcinoma. Clin Can-

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

cer Res. 2013;19(21):5994-6005. https://doi.org/10.1158/1078-0432.

ccr-12-3497

Li Q, Lao X, Pan Q, et al. Adoptive transfer of tumour reactive B

cells confers host T-cell immunity and tumour regression. Clin

Cancer Res. 2011;17(15):4987-4995. https://doi.org/10.1158/10780432.CCR-11-0207

Li Q, Teitz-Tennenbaum S, Donald EJ, Li M, Chang AE. In

vivo sensitized and in vitro activated B cells mediate tumour

regression in cancer adoptive immunotherapy. J Immunol.

2009;183(5):3195-3203.

https://doi.org/10.4049/jimmunol.

0803773

Deng L, Zhang H, Luan Y, et al. Accumulation of foxp3+ T

regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer

patients. Clin Cancer Res. 2010;16(16):4105-4112. https://doi.org/

10.1158/1078-0432.CCR-10-1073

Wu SZ, Al-Eryani G, Roden DL, et al. A single-cell and

spatially resolved atlas of human breast cancers. Nat Genet.

2021;53(9):1334-1347. https://doi.org/10.1038/s41588-021-00911-1

Corridoni D, Antanaviciute A, Gupta T, et al. Single-cell

atlas of colonic CD8(+) T cells in ulcerative colitis. Nat Med.

2020;26(9):1480-1490. https://doi.org/10.1038/s41591-020-1003-4

Zheng Y, Chen Z, Han Y, et al. Immune suppressive landscape

in the human oesophageal squamous cell carcinoma microenvironment. Nat Commun. 2020;11(1):6268. https://doi.org/10.1038/

s41467-020-20019-0

Zhang M, Hu S, Min M, et al. Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell

RNA sequencing. Gut. 2021;70(3):464-475. https://doi.org/10.

1136/gutjnl-2019-320368

McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial

nearest neighbors. Cell Syst. 2019;8(4):329-337. https://doi.org/

10.1016/j.cels.2019.03.003. e4.

Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single-cell data with harmony. Nat Methods.

2019;16(12):1289-1296. https://doi.org/10.1038/s41592-019-0619-0

Black S, Phillips D, Hickey JW, et al. CODEX multiplexed

tissue imaging with DNA-conjugated antibodies. Nat Protoc.

2021;16(8):3802-3835. https://doi.org/10.1038/s41596-021-005568

Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologistoriented resource for the analysis of systems-level datasets.

Nat Commun. 2019;10(1):1523. https://doi.org/10.1038/s41467019-09234-6

Korotkevich G, Sukhov V, Budin N, Shpak B, Artyomov MN,

Sergushichev A, Fast gene set enrichment analysis. Cold Spring

Harbor Laboratory; 2016.

Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced

web server for large-scale expression profiling and interactive

analysis. Nucleic Acids Res. 2019;47(W1):W556-W560. https://

doi.org/10.1093/nar/gkz430

Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in

the bone tissue - a review. Diagn Pathol. 2014;9:221. https://doi.

org/10.1186/s13000-014-0221-9

Ellebedy AH, Jackson KJ, Kissick HT, et al. Defining antigenspecific plasmablast and memory B cell subsets in human

20011326, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1181 by Kyushu University, Wiley Online Library on [17/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

NAKAMURA et al.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

blood after viral infection or vaccination. Nat Immunol.

2016;17(10):1226-1234. https://doi.org/10.1038/ni.3533

Soro PG, Morales AP, Martinez MJ, et al. Differential involvement of the transcription factor Blimp-1 in T cell-independent

and -dependent B cell differentiation to plasma cells. J Immunol.

1999;163(2):611-617.

Cao J, Spielmann M, Qiu X, et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature.

2019;566(7745):496-502.

https://doi.org/10.1038/s41586-0190969-x

Sautes-Fridman C, Verneau J, Sun CM, et al. Tertiary Lymphoid

Structures and B cells: clinical impact and therapeutic modulation in cancer. Semin Immunol. 2020;48:101406. https://doi.org/

10.1016/j.smim.2020.101406

Bao Y, Cao X. The immune potential and immunopathology

of cytokine-producing B cell subsets: a comprehensive review.

J Autoimmun. 2014;55:10-23. https://doi.org/10.1016/j.jaut.2014.

04.001

Holmes AB, Corinaldesi C, Shen Q, et al. Single-cell analysis of

germinal-center B cells informs on lymphoma cell of origin and

outcome. J Exp Med. 2020;217(10):e20200483. https://doi.org/10.

1084/jem.20200483

Liu B, Lin Y, Yan J, et al. Affinity-coupled CCL22 promotes positive selection in germinal centres. Nature. 2021;592(7852):133137. https://doi.org/10.1038/s41586-021-03239-2

Siebenlist U, Brown K, Claudio E. Control of lymphocyte

development by nuclear factor-kappaB. Nat Rev Immunol.

2005;5(6):435-445. https://doi.org/10.1038/nri1629

Ward-Kavanagh LK, Lin WW, Sedy JR, Ware CF. The

TNF receptor superfamily in co-stimulating and coinhibitory

responses.

Immunity.

2016;44(5):1005-1019.

https://doi.org/10.1016/j.immuni.2016.04.019

Corcoran L, Emslie D, Kratina T, et al. Oct2 and Obf1 as facilitators of B:t cell collaboration during a humoral immune response.

Front Immunol. 2014;5:108. https://doi.org/10.3389/fimmu.2014.

00108

Harjunpaa H, Llort Asens M, Guenther C, Fagerholm SC.

Cell adhesion molecules and their roles and regulation in

the immune and tumour microenvironment. Front Immunol.

2019;10:1078. https://doi.org/10.3389/fimmu.2019.01078

Ryan EJ, Marshall AJ, Magaletti D, et al. Dendritic cellassociated lectin-1: a novel dendritic cell-associated, C-type

lectin-like molecule enhances T cell secretion of IL-4. J

Immunol. 2002;169(10):5638-5648. https://doi.org/10.4049/

jimmunol.169.10.5638

Kiefer K, Oropallo MA, Cancro MP, Marshak-Rothstein A. Role

of type I interferons in the activation of autoreactive B cells.

Immunol Cell Biol. 2012;90(5):498-504. https://doi.org/10.1038/

icb.2012.10

Cyster JG, Allen CDC. B cell responses: cell interaction dynamics and decisions. Cell. 2019;177(3):524-540. https://doi.org/10.

1016/j.cell.2019.03.016

Hipp N, Symington H, Pastoret C, et al. IL-2 imprints human

naive B cell fate towards plasma cell through ERK/ELK1mediated BACH2 repression. Nat Commun. 2017;8(1):1443.

https://doi.org/10.1038/s41467-017-01475-7

Tsubata T. Inhibitory B cell co-receptors and autoimmune

diseases. Immunol Med. 2019;42(3):108-116. https://doi.org/10.

1080/25785826.2019.1660038

NAKAMURA et al.

45. Kaileh M, Sen R. NF-kappaB function in B lymphocytes.

Immunol Rev. 2012;246(1):254-271. https://doi.org/10.1111/j.1600065X.2012.01106.x

46. Gu Y, Liu Y, Fu L, et al. Tumour-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting

IgG. Nat Med. 2019;25(2):312-322. https://doi.org/10.1038/s41591018-0309-y

47. Wouters MCA, Nelson BH. Prognostic significance of tumourinfiltrating B cells and plasma cells in human cancer. Clin

Cancer Res. 2018;24(24):6125-6135. https://doi.org/10.1158/10780432.CCR-18-1481

48. Dullaers M, Li D, Xue Y, et al. A T cell-dependent mechanism

for the induction of human mucosal homing immunoglobulin

A-secreting plasmablasts. Immunity. 2009;30(1):120-129. https://

doi.org/10.1016/j.immuni.2008.11.008

49. Sullivan NL, Eickhoff CS, Zhang X, Giddings OK,

Lane TE, Hoft DF. Importance of the CCR5-CCL5

axis for mucosal Trypanosoma cruzi protection and

B cell activation. J Immunol. 2011;187(3):1358-1368.

https://doi.org/10.4049/jimmunol.1100033

50. Zarnegar B, He JQ, Oganesyan G, Hoffmann A, Baltimore D,

Cheng G. Unique CD40-mediated biological program in B cell

activation requires both type 1 and type 2 NF-kappaB activation pathways. Proc Natl Acad Sci U S A. 2004;101(21):8108-8113.

https://doi.org/10.1073/pnas.0402629101

51. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ.

Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229(1):152-172.

https://doi.org/10.1111/j.1600-065X.2009.00782.x

52. Clatza A, Bonifaz LC, Vignali DA, Moreno J. CD40-induced

aggregation of MHC class II and CD80 on the cell surface leads to an early enhancement in antigen presentation. J Immunol. 2003;171(12):6478-6487. https://doi.org/10.

4049/jimmunol.171.12.6478

53. Lo CS, Sanii S, Kroeger DR, et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumourinfiltrating lymphocyte response with distinct implications for

immunotherapy. Clin Cancer Res. 2017;23(4):925-934. https://

doi.org/10.1158/1078-0432.CCR-16-1433

54. Lin X, Ye L, Wang X, et al. Follicular helper T cells remodel the

immune microenvironment of pancreatic cancer via secreting

CXCL13 and IL-21. Cancers (Basel). 2021;13(15):3678. https://doi.

org/10.3390/cancers13153678

55. Montfort A, Pearce O, Maniati E, et al. A strong B-cell response

is part of the immune landscape in human high-grade serous

ovarian metastases. Clin Cancer Res. 2017;23(1):250-262. https://

doi.org/10.1158/1078-0432.CCR-16-0081

56. Lin Q, Tao P, Wang J, et al. Tumour-associated tertiary lymphoid structure predicts postoperative outcomes in patients

with primary gastrointestinal stromal tumours. Oncoimmunology. 2020;9(1):1747339. https://doi.org/10.1080/2162402X.2020.

1747339

57. Meylan M, Petitprez F, Becht E, et al. Tertiary lymphoid structures generate and propagate anti-tumour antibody-producing

plasma cells in renal cell cancer. Immunity. 2022;55(3):527-541.

https://doi.org/10.1016/j.immuni.2022.02.001

58. Schmidt M, Hellwig B, Hammad S, et al. A comprehensive

analysis of human gene expression profiles identifies stromal

immunoglobulin kappa C as a compatible prognostic marker

20011326, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1181 by Kyushu University, Wiley Online Library on [17/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

22 of 23

59.

60.

61.

62.

63.

in human solid tumours. Clin Cancer Res. 2012;18(9):2695-2703.

https://doi.org/10.1158/1078-0432.CCR-11-2210

Bolotin DA, Poslavsky S, Davydov AN, et al. Antigen receptor

repertoire profiling from RNA-seq data. Nature Biotechnology.

2017;35(10):908-911. https://doi.org/10.1038/nbt.3979

Wei Y, Huang CX, Xiao X, et al. B cell heterogeneity, plasticity,

and functional diversity in cancer microenvironments. Oncogene. 2021;40(29):4737-4745. https://doi.org/10.1038/s41388-02101918-y

Shao Y, Geng Y, Gu W, et al. Assessment of lymph node ratio

to replace the pN categories system of classification of the

TNM system in oesophageal squamous cell carcinoma. J Thorac

Oncol. 2016;11(10):1774-1784. https://doi.org/10.1016/j.jtho.2016.

06.019

Cho Y, Miyamoto M, Kato K, et al. CD4+ and CD8+ T cells

cooperate to improve prognosis of patients with oesophageal

squamous cell carcinoma. Cancer Res. 2003;63(7):15551559.

Sudo N, Ichikawa H, Muneoka Y, et al. Clinical utility of ypTNM

stage grouping in the 8th edition of the American Joint Committee on Cancer TNM Staging System for Oesophageal Squamous

Cell Carcinoma. Ann Surg Oncol. 2021;28(2):650-660. https://

doi.org/10.1245/s10434-020-09181-3

23 of 23

64. Yakirevich E, Lu S, Allen D, et al. Prognostic significance of

IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for oesophageal adenocarcinoma. Hum Pathol.

2017;66:126-135. https://doi.org/10.1016/j.humpath.2017.06.009

S U P P O RT I N G I N F O R M AT I O N

Additional supporting information can be found online

in the Supporting Information section at the end of this

article.

How to cite this article: Nakamura S, Ohuchida

K, Ohtsubo Y, et al. Single-cell transcriptome

analysis reveals functional changes in

tumour-infiltrating B lymphocytes after

chemotherapy in oesophageal squamous cell

carcinoma. Clin Transl Med. 2023;13:e1181.

https://doi.org/10.1002/ctm2.1181

20011326, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1181 by Kyushu University, Wiley Online Library on [17/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

NAKAMURA et al.

...

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る