UMMS Affiliation

RNA Therapeutics Institute

Publication Date

2021-09-01

Document Type

Article

Disciplines

Cancer Biology | Immunotherapy | Neoplasms

Abstract

BACKGROUND: Our previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCeta) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCeta-deficient (Prkch (-/-)) Tregs into Prkch (+/+) mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context.

METHODS: We have analyzed the role of PKCeta in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8(+) T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs).

RESULTS: Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16-F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8(+) effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8(+) T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8(+) effector T cells, consistent with findings that Prkch (-/-) CD8(+) T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16-F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies.

CONCLUSION: These findings demonstrate the potential utility of PKCeta inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.

Keywords

CD8-positive T lymphocytes, CTLA4 antigen, combined modality therapy, melanoma, tumor microenvironment

Rights and Permissions

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. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

DOI of Published Version

10.1136/jitc-2021-002792

Source

Liu HY, Pedros C, Kong KF, Canonigo-Balancio AJ, Xue W, Altman A. Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy. J Immunother Cancer. 2021 Sep;9(9):e002792. doi: 10.1136/jitc-2021-002792. PMID: 34588224; PMCID: PMC8483050. Link to article on publisher's site

Journal/Book/Conference Title

Journal for immunotherapy of cancer

Related Resources

Link to Article in PubMed

PubMed ID

34588224

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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