Response to primary chemoradiotherapy of locally advanced oropharyngeal carcinoma is determined by the degree of cytotoxic T cell infiltration within tumor cell aggregates.
CD8 T cells
head-and-neck cancer
multiplex immunohistochemistry
oropharyngeal squamous cell carcinoma
radiotherapy
spatial tumor biology
tumor microenvironment
tumor stem cells
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
14
10
2022
accepted:
13
04
2023
medline:
17
5
2023
pubmed:
16
5
2023
entrez:
15
5
2023
Statut:
epublish
Résumé
Effective anti-tumor immune responses are mediated by T cells and require organized, spatially coordinated interactions within the tumor microenvironment (TME). Understanding coordinated T-cell-behavior and deciphering mechanisms of radiotherapy resistance mediated by tumor stem cells will advance risk stratification of oropharyngeal cancer (OPSCC) patients treated with primary chemoradiotherapy (RCTx). To determine the role of CD8 T cells (CTL) and tumor stem cells for response to RCTx, we employed multiplex immunofluorescence stains on pre-treatment biopsy specimens from 86 advanced OPSCC patients and correlated these quantitative data with clinical parameters. Multiplex stains were analyzed at the single-cell level using QuPath and spatial coordination of immune cells within the TME was explored using the R-package Spatstat. Our observations demonstrate that a strong CTL-infiltration into the epithelial tumor compartment (HR for overall survival, OS: 0.35; p<0.001) and the expression of PD-L1 on CTL (HR: 0.36; p<0.001) were both associated with a significantly better response and survival upon RCTx. As expected, p16 expression was a strong predictor of improved OS (HR: 0.38; p=0.002) and correlated with overall CTL infiltration (r: 0.358, p<0.001). By contrast, tumor cell proliferative activity, expression of the tumor stem cell marker CD271 and overall CTL infiltration, regardless of the affected compartment, were not associated with response or survival. In this study, we could demonstrate the clinical relevance of the spatial organization and the phenotype of CD8 T cells within the TME. In particular, we found that the infiltration of CD8 T cells specifically into the tumor cell compartment was an independent predictive marker for response to chemoradiotherapy, which was strongly associated with p16 expression. Meanwhile, tumor cell proliferation and the expression of stem cell markers showed no independent prognostic effect for patients with primary RCTx and thus requires further study.
Sections du résumé
Background
Effective anti-tumor immune responses are mediated by T cells and require organized, spatially coordinated interactions within the tumor microenvironment (TME). Understanding coordinated T-cell-behavior and deciphering mechanisms of radiotherapy resistance mediated by tumor stem cells will advance risk stratification of oropharyngeal cancer (OPSCC) patients treated with primary chemoradiotherapy (RCTx).
Methods
To determine the role of CD8 T cells (CTL) and tumor stem cells for response to RCTx, we employed multiplex immunofluorescence stains on pre-treatment biopsy specimens from 86 advanced OPSCC patients and correlated these quantitative data with clinical parameters. Multiplex stains were analyzed at the single-cell level using QuPath and spatial coordination of immune cells within the TME was explored using the R-package Spatstat.
Results
Our observations demonstrate that a strong CTL-infiltration into the epithelial tumor compartment (HR for overall survival, OS: 0.35; p<0.001) and the expression of PD-L1 on CTL (HR: 0.36; p<0.001) were both associated with a significantly better response and survival upon RCTx. As expected, p16 expression was a strong predictor of improved OS (HR: 0.38; p=0.002) and correlated with overall CTL infiltration (r: 0.358, p<0.001). By contrast, tumor cell proliferative activity, expression of the tumor stem cell marker CD271 and overall CTL infiltration, regardless of the affected compartment, were not associated with response or survival.
Conclusion
In this study, we could demonstrate the clinical relevance of the spatial organization and the phenotype of CD8 T cells within the TME. In particular, we found that the infiltration of CD8 T cells specifically into the tumor cell compartment was an independent predictive marker for response to chemoradiotherapy, which was strongly associated with p16 expression. Meanwhile, tumor cell proliferation and the expression of stem cell markers showed no independent prognostic effect for patients with primary RCTx and thus requires further study.
Identifiants
pubmed: 37187729
doi: 10.3389/fimmu.2023.1070203
pmc: PMC10175951
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1070203Informations de copyright
Copyright © 2023 Haist, Kaufmann, Kur, Zimmer, Grabbe, Schmidberger, Weigert and Mayer.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Radiother Oncol. 2022 Mar;168:138-146
pubmed: 35093407
Radiat Oncol. 2014 Jan 14;9:23
pubmed: 24423415
Br J Cancer. 2014 Jan 21;110(2):489-500
pubmed: 24169344
N Engl J Med. 2010 Jul 1;363(1):24-35
pubmed: 20530316
Int J Radiat Oncol Biol Phys. 2016 Mar 1;94(3):461-8
pubmed: 26867875
J Immunother Cancer. 2022 Feb;10(2):
pubmed: 35217577
Br J Cancer. 2015 Sep 15;113(6):886-93
pubmed: 26313665
Cancers (Basel). 2021 Aug 02;13(15):
pubmed: 34359786
Nat Commun. 2017 Sep 19;8(1):592
pubmed: 28928380
PLoS Biol. 2021 Apr 26;19(4):e3001199
pubmed: 33901179
N Engl J Med. 1993 Jan 21;328(3):159-63
pubmed: 8417381
Carcinogenesis. 2020 Jun 17;41(4):458-466
pubmed: 31742606
J Clin Oncol. 2010 Sep 20;28(27):4142-8
pubmed: 20697079
Int J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):721-9
pubmed: 25752384
Int J Radiat Oncol Biol Phys. 2012 Aug 1;83(5):1514-20
pubmed: 22270174
Cancer Cell Int. 2020 Dec 7;20(1):583
pubmed: 33372595
Cancer Discov. 2019 Oct;9(10):1422-1437
pubmed: 31340937
Cancer Med. 2019 Jan;8(1):80-93
pubmed: 30600646
Int J Cancer. 2016 Jan 1;138(1):171-81
pubmed: 26178914
Int J Cancer. 2003 Nov 10;107(3):394-400
pubmed: 14506739
Nat Methods. 2022 Jun;19(6):759-769
pubmed: 35654951
Oncoimmunology. 2020 Mar 3;9(1):1729299
pubmed: 32313717
Sci Rep. 2016 Nov 14;6:36956
pubmed: 27841362
Sci Transl Med. 2012 Mar 28;4(127):127ra37
pubmed: 22461641
Br J Cancer. 2022 Jun;126(11):1589-1594
pubmed: 35043007
Methods. 2014 Nov;70(1):46-58
pubmed: 25242720
iScience. 2022 Jan 19;25(2):103785
pubmed: 35146396
Oncotarget. 2017 Jul 06;8(46):80443-80452
pubmed: 29113315
Oncoimmunology. 2018 Jul 30;7(10):e1498439
pubmed: 30288365
Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):43-50
pubmed: 15093897
Cancers (Basel). 2021 Apr 16;13(8):
pubmed: 33923522
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
pubmed: 17210912
Cell. 2020 Jul 23;182(2):497-514.e22
pubmed: 32579974
Nature. 2014 Nov 27;515(7528):568-71
pubmed: 25428505
Cancer Res. 2020 Oct 15;80(20):4414-4425
pubmed: 32699134
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Nature. 2014 Nov 27;515(7528):563-7
pubmed: 25428504
Oral Oncol. 2017 Jul;70:34-42
pubmed: 28622889
Nat Commun. 2022 Apr 21;13(1):2176
pubmed: 35449134
Stem Cell Res Ther. 2010 Dec 14;1(5):39
pubmed: 21156086
Oncogene. 2019 May;38(21):4047-4060
pubmed: 30705400
Cancer Immunol Res. 2018 Oct;6(10):1260-1273
pubmed: 30012633
Cell. 2020 Sep 3;182(5):1341-1359.e19
pubmed: 32763154
J Clin Oncol. 2009 Apr 20;27(12):1992-8
pubmed: 19289615
Oncogenesis. 2017 Jan 23;6(1):e291
pubmed: 28112719
Sci Rep. 2019 Sep 16;9(1):13341
pubmed: 31527658
Oral Oncol. 2013 Mar;49(3):269-76
pubmed: 23089460
Immunity. 2020 Jan 14;52(1):183-199.e9
pubmed: 31924475
Nat Rev Clin Oncol. 2022 May;19(5):306-327
pubmed: 35105976
Oral Oncol. 2014 Sep;50(9):802-8
pubmed: 25043882
Front Oncol. 2019 Oct 01;9:936
pubmed: 31632901
Nat Rev Cancer. 2008 Jul;8(7):545-54
pubmed: 18511937
Oral Oncol. 2018 Nov;86:81-90
pubmed: 30409325
Nat Commun. 2019 Sep 2;10(1):3959
pubmed: 31477729
Cancers (Basel). 2020 Dec 13;12(12):
pubmed: 33322215
Nat Immunol. 2020 Apr;21(4):442-454
pubmed: 32152508
Br J Cancer. 2016 Nov 22;115(11):1351-1358
pubmed: 27802455
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5336-41
pubmed: 12697896
JCI Insight. 2016 Oct 20;1(17):e89829
pubmed: 27777979
Sci Rep. 2019 Sep 16;9(1):13404
pubmed: 31527697
Nature. 2017 Jan 18;541(7637):321-330
pubmed: 28102259
Oncotarget. 2014 Dec 15;5(23):11986-97
pubmed: 25230277
Ann Oncol. 2010 Oct;21(10):1961-1966
pubmed: 20423915
J Immunother Cancer. 2020 Jun;8(1):
pubmed: 32527931
Acta Oncol. 2019 Oct;58(10):1489-1494
pubmed: 31510843
Mol Cancer Res. 2018 Jan;16(1):90-102
pubmed: 28928286
Radiother Oncol. 2018 Jan;126(1):107-115
pubmed: 29100700
Head Neck. 2020 Aug;42(8):2099-2105
pubmed: 32196826
Cancer Res. 2013 Mar 15;73(6):1733-41
pubmed: 23288508
Int J Oral Sci. 2021 Aug 2;13(1):24
pubmed: 34341329