Item request has been placed!
×
Item request cannot be made.
×
Processing Request
Phosphodiesterase-5 inhibition collaborates with vaccine-based immunotherapy to reprogram myeloid cells in pancreatic ductal adenocarcinoma.
Item request has been placed!
×
Item request cannot be made.
×
Processing Request
- Additional Information
- Source:
Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
- Publication Information:
Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
- Subject Terms:
- Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and inducible NOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors, including head and neck cancers. We show for the first time to our knowledge that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-programmed cell death protein 1, and anti-cytotoxic T lymphocyte-associated protein 4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA-sequencing analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid/T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid/T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.
- References:
Clin Cancer Res. 2019 Sep 15;25(18):5493-5502. (PMID: 31126960)
J Exp Med. 2006 Nov 27;203(12):2691-702. (PMID: 17101732)
Cancer Discov. 2021 Aug;11(8):2014-2031. (PMID: 33727309)
Front Immunol. 2020 Nov 10;11:605619. (PMID: 33304355)
Cytometry A. 2015 Jul;87(7):636-45. (PMID: 25573116)
Nat Protoc. 2020 Jul;15(7):2247-2276. (PMID: 32561888)
Science. 2022 Jan 07;375(6576):eabf9419. (PMID: 34990248)
Immunity. 2005 Nov;23(5):539-50. (PMID: 16286021)
J Clin Invest. 2023 Jul 3;133(13):. (PMID: 37395271)
Leukemia. 2021 Dec;35(12):3482-3496. (PMID: 34021248)
J Clin Oncol. 2015 Apr 20;33(12):1325-33. (PMID: 25584002)
Front Cell Dev Biol. 2020 May 19;8:351. (PMID: 32509781)
STAR Protoc. 2023 Mar 17;4(1):101949. (PMID: 36538397)
Nat Biomed Eng. 2021 Oct;5(10):1228-1238. (PMID: 34341534)
JCI Insight. 2021 Apr 8;6(7):. (PMID: 33690223)
Cancer Immunol Res. 2014 Aug;2(8):725-31. (PMID: 24878583)
Signal Transduct Target Ther. 2021 Oct 7;6(1):362. (PMID: 34620838)
Cell Rep. 2021 Jul 20;36(3):109422. (PMID: 34289373)
CA Cancer J Clin. 2020 Jan;70(1):7-30. (PMID: 31912902)
Genome Biol. 2019 Dec 23;20(1):296. (PMID: 31870423)
Gut. 2018 Jun;67(6):1112-1123. (PMID: 29196437)
Front Immunol. 2023 Sep 12;14:1258538. (PMID: 37771596)
Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119)
Trends Immunol. 2004 Jan;25(1):33-9. (PMID: 14698282)
Cancers (Basel). 2019 Oct 24;11(11):. (PMID: 31652904)
Cold Spring Harb Perspect Med. 2020 May 1;10(5):. (PMID: 31548218)
Clin Cancer Res. 2020 Jul 15;26(14):3578-3588. (PMID: 32273276)
F1000Res. 2017 May 26;6:748. (PMID: 28663787)
Cancer Res. 2013 Feb 1;73(3):1128-41. (PMID: 23221383)
Immunity. 2018 Jul 17;49(1):178-193.e7. (PMID: 29958801)
Cancer Res. 2014 Jun 1;74(11):2913-21. (PMID: 24840647)
iScience. 2022 Oct 09;25(11):105317. (PMID: 36310582)
J Transl Med. 2011 Jun 09;9:90. (PMID: 21658270)
J Exp Med. 2013 Mar 11;210(3):465-73. (PMID: 23420877)
Clin Cancer Res. 2015 Jan 1;21(1):39-48. (PMID: 25320361)
Cancer Immunol Res. 2017 Jan;5(1):3-8. (PMID: 28052991)
Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021)
Clin Cancer Res. 2015 Jan 1;21(1):30-8. (PMID: 25564570)
Nat Biotechnol. 2018 Dec 03;:. (PMID: 30531897)
Breast Cancer Res Treat. 2017 Nov;166(1):95-107. (PMID: 28730338)
Nature. 2001 Dec 20-27;414(6866):916-20. (PMID: 11780065)
Nat Rev Cancer. 2023 Apr;23(4):216-237. (PMID: 36747021)
Clin Cancer Res. 2012 Feb 1;18(3):858-68. (PMID: 22147941)
Cancer Commun (Lond). 2023 Jan;43(1):3-41. (PMID: 36424360)
Clin Cancer Res. 2020 Oct 1;26(19):5129-5139. (PMID: 32591464)
Genome Biol. 2015 Dec 10;16:278. (PMID: 26653891)
Annu Rev Immunol. 2004;22:657-82. (PMID: 15032592)
Cell Rep. 2017 Apr 4;19(1):203-217. (PMID: 28380359)
Nat Protoc. 2020 Apr;15(4):1484-1506. (PMID: 32103204)
Gastroenterology. 2014 Jun;146(7):1784-94.e6. (PMID: 24607504)
Curr Urol Rep. 2003 Dec;4(6):457-65. (PMID: 14622499)
- Grant Information:
P01 CA247886 United States CA NCI NIH HHS; U54 CA274371 United States CA NCI NIH HHS; T32 GM148383 United States GM NIGMS NIH HHS; F31 CA268724 United States CA NCI NIH HHS; R21 CA264004 United States CA NCI NIH HHS
- Contributed Indexing:
Keywords: Cancer immunotherapy; Immunology; Immunotherapy; Oncology; Phosphodiesterases
- Accession Number:
742SXX0ICT (Tadalafil)
0 (Cancer Vaccines)
0 (Phosphodiesterase 5 Inhibitors)
J27WDC343N (Mesothelin)
- Publication Date:
Date Created: 20240806 Date Completed: 20240924 Latest Revision: 20241009
- Publication Date:
20241009
- Accession Number:
PMC11457845
- Accession Number:
10.1172/jci.insight.179292
- Accession Number:
39106104
No Comments.