BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma.
antigen presentation
dendritic cells
immunotherapy
macrophages
melanoma
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:
06 2022
06 2022
Historique:
accepted:
13
05
2022
entrez:
22
6
2022
pubmed:
23
6
2022
medline:
25
6
2022
Statut:
ppublish
Résumé
The use of intralesional We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8 Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8 These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.
Sections du résumé
BACKGROUND
The use of intralesional
METHODS
We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8
RESULTS
Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8
CONCLUSIONS
These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.
Identifiants
pubmed: 35732347
pii: jitc-2021-004133
doi: 10.1136/jitc-2021-004133
pmc: PMC9226922
pii:
doi:
Substances chimiques
BCG Vaccine
0
Hydrogels
0
Receptors, Antigen, T-Cell
0
Cathepsins
EC 3.4.-
cathepsin S
EC 3.4.22.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Nat Immunol. 2017 Feb 15;18(3):255-262
pubmed: 28198830
Infect Immun. 2000 Dec;68(12):6883-90
pubmed: 11083809
Sci Rep. 2015 Aug 25;5:13351
pubmed: 26302899
J Immunol. 2008 Mar 15;180(6):4308-15
pubmed: 18322244
Cell. 2018 Apr 5;173(2):283-285
pubmed: 29625045
Trends Immunol. 2002 Nov;23(11):549-55
pubmed: 12401408
Br J Dermatol. 2017 Jul;177(1):134-140
pubmed: 28369739
Appl Microbiol Biotechnol. 2019 Oct;103(19):7903-7916
pubmed: 31402426
Oncogene. 2010 Feb 25;29(8):1093-102
pubmed: 19946335
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
J Transl Med. 2010 Jan 15;8:4
pubmed: 20078880
Cell. 2017 Feb 9;168(4):707-723
pubmed: 28187290
Immunity. 1996 Apr;4(4):357-66
pubmed: 8612130
Front Immunol. 2017 Aug 11;8:965
pubmed: 28848560
Immunity. 2004 Aug;21(2):155-65
pubmed: 15308097
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9
pubmed: 8170938
Blood. 2015 Mar 26;125(13):2079-86
pubmed: 25662332
Trends Immunol. 2015 Nov;36(11):738-749
pubmed: 26508293
Bioinformatics. 2009 Apr 15;25(8):1091-3
pubmed: 19237447
Nanoscale. 2018 Aug 7;10(29):13976-13985
pubmed: 30010686
N Engl J Med. 2012 Jun 28;366(26):2455-65
pubmed: 22658128
Cell. 1994 Jan 14;76(1):17-27
pubmed: 8287475
Blood. 2009 Nov 5;114(19):4099-107
pubmed: 19706884
Cancer Cell. 2016 Aug 8;30(2):324-336
pubmed: 27424807
J Urol. 2014 May;191(5):1422-8
pubmed: 24333111
Expert Opin Drug Deliv. 2011 Aug;8(8):991-1007
pubmed: 21564003
N Engl J Med. 2012 Jun 28;366(26):2443-54
pubmed: 22658127
World Allergy Organ J. 2010 Aug;3(8 Suppl):S17-23
pubmed: 23282746
Blood. 2009 Apr 9;113(15):3546-52
pubmed: 18941113
J Immunol. 1999 May 15;162(10):5838-45
pubmed: 10229818
Mol Cancer Ther. 2003 Mar;2(3):255-63
pubmed: 12657720
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):673-8
pubmed: 16467076
Science. 2008 Nov 14;322(5904):1097-100
pubmed: 19008445
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
J Thorac Cardiovasc Surg. 2007 Jan;133(1):104-10
pubmed: 17198792
J Natl Compr Canc Netw. 2019 Apr 1;17(4):367-402
pubmed: 30959471
Cancer Chemother Rep. 1972 Oct;56(5):659-65
pubmed: 4569059
Sci Rep. 2018 Jan 18;8(1):1058
pubmed: 29348598
J Control Release. 2012 Apr 10;159(1):14-26
pubmed: 22154931
J Immunol. 2017 Sep 1;199(5):1660-1671
pubmed: 28739876
J Oncol. 2012;2012:647684
pubmed: 22792102
N Engl J Med. 2013 Jul 11;369(2):122-33
pubmed: 23724867
Front Oncol. 2017 Apr 05;7:61
pubmed: 28424760
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
J Dermatol Surg Oncol. 1993 Nov;19(11):985-90
pubmed: 8245304
J Exp Med. 1996 Dec 1;184(6):2207-16
pubmed: 8976176
J Exp Med. 1997 Feb 3;185(3):453-9
pubmed: 9053445
Ann Surg. 1974 Oct;180(4):635-43
pubmed: 4412271
J Intern Med. 2020 Dec;288(6):625-640
pubmed: 32128919
Adv Drug Deliv Rev. 2001 Dec 31;53(3):321-39
pubmed: 11744175
J Natl Cancer Inst. 1974 Jan;52(1):95-101
pubmed: 4590014