Overcoming resistance to αPD-1 of MMR-deficient tumors with high tumor-induced neutrophils levels by combination of αCTLA-4 and αPD-1 blockers.
CTLA-4 antigen
genome instability
immunotherapy
neutrophil infiltration
tumor biomarkers
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:
07 2022
07 2022
Historique:
accepted:
30
06
2022
entrez:
27
7
2022
pubmed:
28
7
2022
medline:
30
7
2022
Statut:
ppublish
Résumé
Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood. 4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy. TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.
Sections du résumé
BACKGROUND
Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood.
METHODS
4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene
RESULTS
By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy.
CONCLUSIONS
TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.
Identifiants
pubmed: 35896284
pii: jitc-2022-005059
doi: 10.1136/jitc-2022-005059
pmc: PMC9335020
pii:
doi:
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)) 2022. 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: NC reports grants from Cytune Pharma, grants from BMS, grants from SANOFI, personal fees from AstraZeneca France, outside the submitted work. Other authors declare no conflict of interest with this work.
Références
J Natl Cancer Inst. 2014 May 29;106(6):dju124
pubmed: 24875653
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Science. 2019 May 3;364(6439):485-491
pubmed: 31048490
Oncoimmunology. 2018 Mar 15;7(6):e1433981
pubmed: 29872568
J Leukoc Biol. 2008 Jan;83(1):64-70
pubmed: 17884993
Genome Med. 2017 Apr 19;9(1):34
pubmed: 28420421
J Hepatol. 2021 Dec;75(6):1271-1283
pubmed: 34363921
Cancer Discov. 2015 Jan;5(1):43-51
pubmed: 25358689
Gastroenterology. 2016 Jun;150(7):1646-1658.e17
pubmed: 26924089
Science. 2017 Jul 28;357(6349):409-413
pubmed: 28596308
BMC Genomics. 2019 Aug 30;20(1):685
pubmed: 31470794
Clin Cancer Res. 2016 Feb 15;22(4):813-20
pubmed: 26880610
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21248-55
pubmed: 21081700
Ann Oncol. 2021 May;32(5):661-672
pubmed: 33736924
Neuro Oncol. 2016 Sep;18(9):1253-64
pubmed: 27006175
Bioinformatics. 2012 Oct 1;28(19):2520-2
pubmed: 22908215
Front Immunol. 2021 May 14;12:672271
pubmed: 34054853
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Sci Rep. 2019 Dec 23;9(1):19673
pubmed: 31873162
J Clin Oncol. 2018 Mar 10;36(8):773-779
pubmed: 29355075
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
J Clin Oncol. 2020 Jan 1;38(1):1-10
pubmed: 31682550
Int J Cancer. 2014 Sep 1;135(5):1178-86
pubmed: 24501019
Nature. 2020 Feb;578(7793):94-101
pubmed: 32025018
Bioinformatics. 2016 Oct 1;32(19):3047-8
pubmed: 27312411
Clin Cancer Res. 2011 Nov 15;17(22):6992-7002
pubmed: 21948231
Cell Rep. 2017 Jan 3;18(1):248-262
pubmed: 28052254
Immunity. 2020 Oct 13;53(4):824-839.e10
pubmed: 33053331
PLoS One. 2016 Jun 24;11(6):e0157822
pubmed: 27341421
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
J Immunother Cancer. 2018 Jan 22;6(1):5
pubmed: 29353553
Cancer Discov. 2016 Jun;6(6):630-49
pubmed: 27072748
Mod Pathol. 2019 Apr;32(4):576-584
pubmed: 30401949
Science. 2017 Mar 31;355(6332):1423-1427
pubmed: 28280249
Front Immunol. 2018 Oct 09;9:2100
pubmed: 30356816
J Immunol. 2018 Sep 1;201(5):1389-1399
pubmed: 30021768
Lancet Oncol. 2017 Sep;18(9):1182-1191
pubmed: 28734759
J Exp Med. 2013 Aug 26;210(9):1695-710
pubmed: 23897981
N Engl J Med. 2017 Oct 12;377(15):1409-1412
pubmed: 29020592
Nature. 2017 Jan 18;541(7637):321-330
pubmed: 28102259
J Immunol. 1986 May 1;136(9):3420-6
pubmed: 3007617
Cancer. 2012 Mar 1;118(5):1422-8
pubmed: 21823111
Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33
pubmed: 25431634
Oncoimmunology. 2014 Jun 25;3:e29256
pubmed: 25101223
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Liver Int. 2021 Sep;41(9):2189-2199
pubmed: 33966338
Onco Targets Ther. 2018 Feb 23;11:955-965
pubmed: 29503570
Cancer Immunol Res. 2017 Jan;5(1):29-41
pubmed: 27923825