Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1.
immunotherapy
killer cells
natural
tumor escape
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
accepted:
02
11
2021
entrez:
26
11
2021
pubmed:
27
11
2021
medline:
16
12
2021
Statut:
ppublish
Résumé
Natural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms. NK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models. We found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts. Our work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.
Sections du résumé
BACKGROUND
Natural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms.
METHODS
NK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models.
RESULTS
We found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts.
CONCLUSION
Our work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.
Identifiants
pubmed: 34824159
pii: jitc-2021-003224
doi: 10.1136/jitc-2021-003224
pmc: PMC8627417
pii:
doi:
Substances chimiques
Chil1 protein, mouse
0
Chitinase-3-Like Protein 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
J Immunol. 2007 Sep 1;179(5):2766-73
pubmed: 17709490
Mol Cancer Ther. 2011 May;10(5):742-51
pubmed: 21357475
Eur J Immunol. 1995 Dec;25(12):3514-6
pubmed: 8566046
Mediators Inflamm. 2018 Oct 25;2018:9853192
pubmed: 30498395
Breast Cancer (Dove Med Press). 2017 Mar 21;9:185-198
pubmed: 28356768
J Innate Immun. 2011;3(4):355-64
pubmed: 21502747
Oncoimmunology. 2015 May 29;4(12):e1052353
pubmed: 26587323
Hematol Oncol Stem Cell Ther. 2015 Jun;8(2):47-55
pubmed: 25571788
J Transl Med. 2008 May 16;6:25
pubmed: 18485193
Oncogene. 2017 Aug;36(31):4457-4468
pubmed: 28368410
J Immunother Cancer. 2021 Jan;9(1):
pubmed: 33468562
Clin Breast Cancer. 2018 Jun;18(3):e321-e328
pubmed: 28645722
Mol Cancer Ther. 2007 Jul;6(7):2065-72
pubmed: 17620435
Urol Int. 2018;101(1):65-73
pubmed: 29949801
Cancer Immunol Immunother. 2017 May;66(5):573-579
pubmed: 28197666
Hum Immunol. 2011 Sep;72(9):699-707
pubmed: 21664396
Nat Rev Immunol. 2008 Sep;8(9):713-25
pubmed: 19172692
Growth Factors. 2011 Oct;29(5):187-95
pubmed: 21831009
Cancer Immunol Immunother. 2009 Nov;58(11):1887-96
pubmed: 19340424
Curr Biol. 2009 Dec 1;19(22):1886-96
pubmed: 19913427
Front Immunol. 2015 Jul 27;6:368
pubmed: 26284063
Signal Transduct Target Ther. 2020 Sep 14;5(1):201
pubmed: 32929074
J Exp Clin Cancer Res. 2018 Aug 30;37(1):208
pubmed: 30165890
Eur J Cell Biol. 2006 Apr;85(3-4):165-73
pubmed: 16360240
Cell Commun Signal. 2020 Mar 4;18(1):5
pubmed: 32127023
Oncotarget. 2017 Jan 17;8(3):5382-5391
pubmed: 28036271
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3017-22
pubmed: 18287025
Sci Rep. 2016 May 20;6:26299
pubmed: 27198666
Int J Cancer. 2012 Jul 15;131(2):377-86
pubmed: 21866546
Carcinogenesis. 2009 Jul;30(7):1073-81
pubmed: 19468060
Biochem Soc Trans. 2018 Feb 19;46(1):141-151
pubmed: 29351964
Cell Signal. 2013 Nov;25(11):2185-97
pubmed: 23838007
PLoS One. 2013 Sep 25;8(9):e75366
pubmed: 24086515
PLoS One. 2007 Mar 28;2(3):e326
pubmed: 17389917
J Immunol. 2015 Jun 1;194(11):5539-48
pubmed: 25911757
Oncotarget. 2015 Nov 3;6(34):36535-50
pubmed: 26431492
Front Immunol. 2019 May 31;10:1205
pubmed: 31214177
Clin Exp Metastasis. 2020 Jun;37(3):401-412
pubmed: 32279122
Tumour Biol. 2014 Dec;35(12):12131-7
pubmed: 25142236
Asian Pac J Cancer Prev. ;18(5):1383-1387
pubmed: 28612591
Biochem J. 2002 Jul 1;365(Pt 1):119-26
pubmed: 12071845
In Vitro Cell Dev Biol Anim. 2019 Dec;55(10):838-853
pubmed: 31482369
Oncogene. 1994 Dec;9(12):3417-26
pubmed: 7970700
Front Immunol. 2018 Feb 20;9:307
pubmed: 29515593
Sci Rep. 2018 Oct 9;8(1):15029
pubmed: 30301907
J Exp Med. 2009 May 11;206(5):1149-66
pubmed: 19414556
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6329-34
pubmed: 17395718
Altern Lab Anim. 2002 Dec;30 Suppl 2:217-9
pubmed: 12513679
Cancer Cell. 2017 Aug 14;32(2):135-154
pubmed: 28810142
Cancer Chemother Pharmacol. 2019 Mar;83(3):561-571
pubmed: 30610366
Nat Commun. 2018 Feb 5;9(1):503
pubmed: 29403003
BMC Cancer. 2010 Jun 30;10:340
pubmed: 20591136
J Clin Invest. 2015 Aug 3;125(8):3178-92
pubmed: 26121745
Ann Oncol. 2011 Jun;22(6):1302-1307
pubmed: 21109570
Cell Rep. 2013 Aug 29;4(4):830-41
pubmed: 23972995
Int J Cancer Suppl. 1991;6:38-44
pubmed: 2066183