Transcriptional Activity and Stability of CD39+CD103+CD8+ T Cells in Human High-Grade Endometrial Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 May 31

PMID 32471032

Citations 9

Authors

Hagma H Workel

Nienke van Rooij

Annechien Plat

Diana C J Spierings

Rudolf S N Fehrmann

Hans W Nijman

Marco de Bruyn

Affiliations

Soon will be listed here.

Abstract

Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (T cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific T with enhanced cytolytic potential, suggesting that CD39+CD103+ T could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of T cells in situ. We analyzed CD39+CD103+ T cells sorted from human high-grade endometrial cancers ( = 3) using mRNA sequencing. Cells remained untreated or were incubated with PMA/ionomycin (activation), actinomycin D (a platinum-like chemotherapeutic that inhibits transcription), or a combination of the two. Resting CD39+CD103+ T cells were transcriptionally active and expressed a characteristic T signature. Activated CD39+CD103+ T cells differentially expressed , , and , and cytokine genes , , , (GM-CSF), and . Findings were confirmed using qPCR and cytokine production was validated by flow cytometry of cytotoxic TIL. We studied transcript stability and found that PMA-responsive genes and mitochondrial genes were particularly stable. In conclusion, CD39+CD103+ T cells are transcriptionally active T cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon T reactivation in tumors.

Citing Articles

Tissue-resident memory T cells in diseases and therapeutic strategies.

Xie D, Lu G, Mai G, Guo Q, Xu G MedComm (2020). 2025; 6(1):e70053.

PMID: 39802636 PMC: 11725047. DOI: 10.1002/mco2.70053.

Characterization of purinergic signaling in tumor-infiltrating lymphocytes from lower- and high-grade gliomas.

Scholl J, Weber A, Dias C, Lima V, Grun L, Zambonin D Purinergic Signal. 2023; 20(1):47-64.

PMID: 36964277 PMC: 10828327. DOI: 10.1007/s11302-023-09931-4.

CD39-Expressing CD8 T Cells as a New Molecular Marker for Diagnosis and Prognosis of Esophageal Squamous Cell Carcinoma.

Liu M, Zhao Y, Xiao Z, Zhou R, Chen X, Cui S Cancers (Basel). 2023; 15(4).

PMID: 36831526 PMC: 9954671. DOI: 10.3390/cancers15041184.

The roles and clinical applications of interleukins in endometrial carcinoma.

Zang Y, Li H, Liu S, Zhao R, Zhang K, Zang Y Front Oncol. 2022; 12:1001693.

PMID: 36531027 PMC: 9748080. DOI: 10.3389/fonc.2022.1001693.

Potential biomarkers: Identifying powerful tumor specific T cells in adoptive cellular therapy.

Ge W, Dong Y, Deng Y, Chen L, Chen J, Liu M Front Immunol. 2022; 13:1003626.

PMID: 36451828 PMC: 9702804. DOI: 10.3389/fimmu.2022.1003626.

References

Novy P, Huang X, Leonard W, Yang Y . Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. J Immunol. 2011; 186(5):2729-38. PMC: 3059504. DOI: 10.4049/jimmunol.1003009. View

Xiao L, Jia L, Bai L, He L, Yang B, Wu C . Phenotypic and functional characteristics of IL-21-expressing CD8(+) T cells in human nasal polyps. Sci Rep. 2016; 6:30362. PMC: 4965861. DOI: 10.1038/srep30362. View

Lo C, Sanii S, Kroeger D, Milne K, Talhouk A, Chiu D . Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy. Clin Cancer Res. 2016; 23(4):925-934. DOI: 10.1158/1078-0432.CCR-16-1433. View

Komdeur F, Prins T, van de Wall S, Plat A, Wisman G, Hollema H . CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. Oncoimmunology. 2017; 6(9):e1338230. PMC: 5599086. DOI: 10.1080/2162402X.2017.1338230. View

McNamara M, Nair S, Holl E . RNA-Based Vaccines in Cancer Immunotherapy. J Immunol Res. 2015; 2015:794528. PMC: 4668311. DOI: 10.1155/2015/794528. View

McAlpine J, Leon-Castillo A, Bosse T . The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol. 2018; 244(5):538-549. DOI: 10.1002/path.5034. View

Guo X, Zhang Y, Zheng L, Zheng C, Song J, Zhang Q . Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018; 24(7):978-985. DOI: 10.1038/s41591-018-0045-3. View

Chen Y, Yu M, Zheng Y, Fu G, Xin G, Zhu W . CXCR5PD-1 follicular helper CD8 T cells control B cell tolerance. Nat Commun. 2019; 10(1):4415. PMC: 6765049. DOI: 10.1038/s41467-019-12446-5. View

Ahmed A, Thompson J, Emiliusen L, Murphy S, Beauchamp R, Suzuki K . A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization. Nat Biotechnol. 2003; 21(7):771-7. DOI: 10.1038/nbt835. View

10.

Collins S, Waickman A, Basson A, Kupfer A, Licht J, Horton M . Regulation of CD4⁺ and CD8⁺ effector responses by Sprouty-1. PLoS One. 2012; 7(11):e49801. PMC: 3499516. DOI: 10.1371/journal.pone.0049801. View

11.

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

12.

Takenaka M, Robson S, Quintana F . Regulation of the T Cell Response by CD39. Trends Immunol. 2016; 37(7):427-439. PMC: 5215082. DOI: 10.1016/j.it.2016.04.009. View

13.

Ganesan A, Clarke J, Wood O, Garrido-Martin E, Chee S, Mellows T . Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017; 18(8):940-950. PMC: 6036910. DOI: 10.1038/ni.3775. View

14.

Bhattacharya A, Bense R, Urzua-Traslavina C, de Vries E, van Vugt M, Fehrmann R . Transcriptional effects of copy number alterations in a large set of human cancers. Nat Commun. 2020; 11(1):715. PMC: 7002723. DOI: 10.1038/s41467-020-14605-5. View

15.

Sahin U, Tureci O . Personalized vaccines for cancer immunotherapy. Science. 2018; 359(6382):1355-1360. DOI: 10.1126/science.aar7112. View

16.

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

17.

Wei X, Chan S, Kwek S, Lewis J, Dao V, Zhang L . Systemic GM-CSF Recruits Effector T Cells into the Tumor Microenvironment in Localized Prostate Cancer. Cancer Immunol Res. 2016; 4(11):948-958. PMC: 5115633. DOI: 10.1158/2326-6066.CIR-16-0042. View

18.

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

19.

Mokrani M, Klibi J, Bluteau D, Bismuth G, Mami-Chouaib F . Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes. J Immunol. 2014; 192(5):2471-9. DOI: 10.4049/jimmunol.1302192. View

20.

Brunekreeft K, Paijens S, Wouters M, Komdeur F, Eggink F, Lubbers J . Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome. Oncoimmunology. 2020; 9(1):1760705. PMC: 7458665. DOI: 10.1080/2162402X.2020.1760705. View