Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep 30;12(10):2828.
doi: 10.3390/cancers12102828.

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Wei Liu  1 , Paweł Stachura  1 , Haifeng C Xu  1 , Sanil Bhatia  2 , Arndt Borkhardt  2 , Philipp A Lang  1 , Aleksandra A Pandyra  1   2   3
Affiliations
Review

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Wei Liu et al. Cancers (Basel). .

Abstract

The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.

Keywords: CD8+ T cells; immunotherapy; metabolism; senescence.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Surface phenotypic, metabolic and transcriptional differences between CD8+ dysfunctional senescent and exhaustive states. Characteristics common to both dysfunctional states are shown the in the middle, purple overlapping section. While both T cell state exhibit decreased effector function, senescent T cells have a very distinct senescence-associated secretory phenotype (SASP) with increased cytokine production of IFN-γ, IL-6, IL-8, IL-10, TNF and TGF-β. In contrast. exhausted T cells are characterized by decreased IL-2, TNF and IFN-γ production. While some surface markers such as Tim-3 and TGIT are common to both dysfunctional T cell states, there is otherwise quite a distinct pattern of expression. Ag = antigen.
Figure 2
Figure 2
T cell senescence can occur via multiple mechanisms within the tumor microenvironment. Tregs, through glucose metabolic competition and transfer of cAMP produced by tumors, can induce CD8+ T cell senescence, as can other metabolites produced by tumor cells, such as adenosine. Repeated antigen stimulation and external factors such as chemotherapeutic and radiation therapy also induce premature senescence. A key molecular pathway involved in CD8+ T cell senescence induction is non-canonical signaling through p38-MAPK.
See this image and copyright information in PMC

References

    1. Waldman A.D., Fritz J.M., Lenardo M.J. A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat. Rev. Immunol. 2020:1–18. doi: 10.1038/s41577-020-0306-5. - DOI - PMC - PubMed
    1. Martinez-Lostao L., Anel A., Pardo J. How Do Cytotoxic Lymphocytes Kill Cancer Cells? Clin. Cancer Res. 2015;21:5047–5056. doi: 10.1158/1078-0432.CCR-15-0685. - DOI - PubMed
    1. Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J.-J., Cowey C.L., Lao C.D., Schadendorf D., Dummer R., Smylie M., Rutkowski P., et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New Engl. J. Med. 2015;373:23–34. doi: 10.1056/NEJMoa1504030. - DOI - PMC - PubMed
    1. Barber D.L., Wherry E.J., Masopust D., Zhu B., Allison J., Sharpe A.H., Freeman G.J., Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–687. doi: 10.1038/nature04444. - DOI - PubMed
    1. Locke F.L., Neelapu S.S., Bartlett N.L., Siddiqi T., Chavez J.C., Hosing C.M., Ghobadi A., Budde L.E., Bot A., Rossi J.M., et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol. Ther. 2017;25:285–295. doi: 10.1016/j.ymthe.2016.10.020. - DOI - PMC - PubMed