Stem-like CD8 T Cells in Cancer

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Aug 30

PMID 39211052

Authors

Chelsea Steiner

Nathan Denlinger

Xiaopei Huang

Yiping Yang

Affiliations

Soon will be listed here.

Abstract

Stem-like CD8 T cells (T) are a subset of immune cells with superior persistence and antitumor immunity. They are TCF1 PD-1 and important for the expansion of tumor specific CD8 T cells in response to checkpoint blockade immunotherapy. In acute infections, naïve CD8 T cells differentiate into effector and memory CD8 T cells; in cancer and chronic infections, persistent antigen stimulation can lead to T cell exhaustion. Recent studies have highlighted the dichotomy between late dysfunctional (or exhausted) T cells (T) that are TCF1 PD-1 and self-renewing TCF1 PD-1 T from which they derive. TCF1 T cells are considered to have stem cell-like properties akin to memory T cell populations and can give rise to cytotoxic effector and transitory T cell phenotypes (T) which mediate tumor control. In this review, we will discuss recent advances made in research on the formation and expansion of T, as well as distinct niches required for their differentiation and maintenance in the setting of cancer. We will also discuss potential strategies to generate these cells, with clinical implications for stemness enhancement in vaccine design, immune checkpoint blockade (ICB), and adoptive T cell therapies.

Citing Articles

DNA methyltransferase 3A: A prognostic biomarker and potential target for immunotherapy in gastric cancer.

Wei Z, Kou Z, Luo Y, Cheng Y Medicine (Baltimore). 2025; 104(7):e41578.

PMID: 39960919 PMC: 11835108. DOI: 10.1097/MD.0000000000041578.

References

Sen D, Kaminski J, Barnitz R, Kurachi M, Gerdemann U, Yates K . The epigenetic landscape of T cell exhaustion. Science. 2016; 354(6316):1165-1169. PMC: 5497589. DOI: 10.1126/science.aae0491. View

Sharpe A, Pauken K . The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2017; 18(3):153-167. DOI: 10.1038/nri.2017.108. View

Simoni Y, Becht E, Fehlings M, Loh C, Koo S, Teng K . Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018; 557(7706):575-579. DOI: 10.1038/s41586-018-0130-2. View

Deng Q, Han G, Puebla-Osorio N, Ma M, Strati P, Chasen B . Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020; 26(12):1878-1887. PMC: 8446909. DOI: 10.1038/s41591-020-1061-7. View

Gattinoni L, Klebanoff C, Palmer D, Wrzesinski C, Kerstann K, Yu Z . Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005; 115(6):1616-26. PMC: 1137001. DOI: 10.1172/JCI24480. View

Denlinger N, Song N, Zhang X, Jeon H, Peterson C, Wang Y . Postinfusion PD-1+ CD8+ CAR T cells identify patients responsive to CD19 CAR T-cell therapy in non-Hodgkin lymphoma. Blood Adv. 2024; 8(12):3140-3153. PMC: 11222947. DOI: 10.1182/bloodadvances.2023012073. View

Brummelman J, Mazza E, Alvisi G, Colombo F, Grilli A, Mikulak J . High-dimensional single cell analysis identifies stem-like cytotoxic CD8 T cells infiltrating human tumors. J Exp Med. 2018; 215(10):2520-2535. PMC: 6170179. DOI: 10.1084/jem.20180684. View

Guo Y, Xie Y, Gao M, Zhao Y, Franco F, Wenes M . Metabolic reprogramming of terminally exhausted CD8 T cells by IL-10 enhances anti-tumor immunity. Nat Immunol. 2021; 22(6):746-756. PMC: 7610876. DOI: 10.1038/s41590-021-00940-2. View

Gebhardt T, Park S, Parish I . Stem-like exhausted and memory CD8 T cells in cancer. Nat Rev Cancer. 2023; 23(11):780-798. DOI: 10.1038/s41568-023-00615-0. View

10.

Chen J, Lopez-Moyado I, Seo H, Lio C, Hempleman L, Sekiya T . NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567(7749):530-534. PMC: 6546093. DOI: 10.1038/s41586-019-0985-x. View

11.

Li Z, Tuong Z, Dean I, Willis C, Gaspal F, Fiancette R . In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue. J Exp Med. 2022; 219(6). PMC: 9048291. DOI: 10.1084/jem.20210749. View

12.

Ando M, Kondo T, Tomisato W, Ito M, Shichino S, Srirat T . Rejuvenating Effector/Exhausted CAR T Cells to Stem Cell Memory-Like CAR T Cells By Resting Them in the Presence of CXCL12 and the NOTCH Ligand. Cancer Res Commun. 2023; 1(1):41-55. PMC: 9973402. DOI: 10.1158/2767-9764.CRC-21-0034. View

13.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang Y . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25):12410-12415. PMC: 6589758. DOI: 10.1073/pnas.1905675116. View

14.

Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C . TCF1 hepatitis C virus-specific CD8 T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017; 8:15050. PMC: 5418623. DOI: 10.1038/ncomms15050. View

15.

Ghoneim H, Fan Y, Moustaki A, Abdelsamed H, Dash P, Dogra P . De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017; 170(1):142-157.e19. PMC: 5568784. DOI: 10.1016/j.cell.2017.06.007. View

16.

Blackburn S, Shin H, Freeman G, Wherry E . Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A. 2008; 105(39):15016-21. PMC: 2567485. DOI: 10.1073/pnas.0801497105. View

17.

Kondo T, Morita R, Okuzono Y, Nakatsukasa H, Sekiya T, Chikuma S . Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy. Nat Commun. 2017; 8:15338. PMC: 5458121. DOI: 10.1038/ncomms15338. View

18.

Sade-Feldman M, Yizhak K, Bjorgaard S, Ray J, de Boer C, Jenkins R . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018; 175(4):998-1013.e20. PMC: 6641984. DOI: 10.1016/j.cell.2018.10.038. View

19.

Scholler N, Perbost R, Locke F, Jain M, Turcan S, Danan C . Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat Med. 2022; 28(9):1872-1882. PMC: 9499856. DOI: 10.1038/s41591-022-01916-x. View

20.

Held W, Siddiqui I, Schaeuble K, Speiser D . Intratumoral CD8 T cells with stem cell-like properties: Implications for cancer immunotherapy. Sci Transl Med. 2019; 11(515). DOI: 10.1126/scitranslmed.aay6863. View