High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention

The Journal of Immunology : Official Journal of the American Association of Immunologists
Petra U PrinzElfriede Noessner

Abstract

CD8(+) tumor-infiltrating T cells (CD8-TILs) are found in many types of tumors including human renal cell carcinoma. However, tumor rejection rarely occurs, suggesting limited functional activity in the tumor microenvironment. In this study, we document that CD8-TILs are unresponsive to CD3 stimulation, showing neither lytic activity, nor lytic granule exocytosis, nor IFN-γ production. Mechanistically, no deficits in TCR proximal signaling molecules (lymphocyte-specific protein tyrosine kinase, phospholipase Cγ) were identified. In contrast, distal TCR signaling was suppressed, as T cells of TILs showed strongly reduced steady-state phosphorylation of the MAPK ERK and were unable to increase phosphorylation of ERK and JNK as well as AKT and AKT client proteins (IκB, GSK3) after stimulation. These deficits were tumor-specific as they were not observed in CD8(+) T cells infiltrating non-tumor kidney areas (CD8(+) non-tumor kidney-infiltrating lymphocytes; CD8-NILs). Diacylglycerol kinase-α (DGK-α) was more highly expressed in CD8-TILs compared with that in CD8-NILs, and its inhibition improved ERK phosphorylation and lytic granule exocytosis. Cultivation of TILs in low-dose IL-2 reduced DGK-α protein levels, increased steady-stat...Continue Reading

References

Jan 1, 1993·Cancer Immunology, Immunotherapy : CII·S M DubinettW H McBride
Jan 23, 1996·Proceedings of the National Academy of Sciences of the United States of America·Q G MedleyP Anderson
Jun 1, 1997·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·D J SchendelE Nössner
Dec 16, 1998·Lancet·N J Vogelzang, W M Stadler
Oct 24, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·S RadojaA B Frey
Jun 28, 2002·Cell·Fernando MaciánAnjana Rao
Oct 29, 2003·Journal of Immunological Methods·Michael R BettsRichard A Koup
Jun 24, 2004·Cellular Signalling·Bai LuoMatthew K Topham
Sep 15, 2005·Cancer Immunology, Immunotherapy : CII·David SchramaJürgen C Becker
Dec 13, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Leslie K RobertsonHanne L Ostergaard
Feb 10, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Julia S SchleypenElfriede Noessner
Jul 22, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jörn DengjelStefan Stevanović
Aug 25, 2006·Critical Reviews in Immunology·Sasa RadojaStanislav Vukmanovic
Sep 16, 2006·Immunological Reviews·Thomas F GajewskiHelena Harlin
May 4, 2007·The Journal of Clinical Investigation·Jeremy B Swann, Mark J Smyth
Jul 3, 2007·Cell·Brendan D Manning, Lewis C Cantley
Jul 28, 2007·Seminars in Cancer Biology·Bernhard FrankenbergerDolores J Schendel
Oct 24, 2007·Current Opinion in Immunology·Samuel D SaibilPamela S Ohashi
Jan 5, 2008·EMBO Reports·Yan ZhengThomas F Gajewski
Feb 16, 2008·Lancet·Alberto MantovaniFrancesco M Marincola
May 7, 2008·Trends in Immunology·Ena WangFrancesco M Marincola
Sep 2, 2008·Immunological Reviews·Xiao-Ping ZhongChi-Keung Wan
Nov 8, 2008·Molecular Immunology·Myrianne Duré, Fernando Macian
Mar 10, 2009·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Christiane GeigerDolores J Schendel
Apr 4, 2009·Cancer Chemotherapy and Pharmacology·David J Reeves, Chin Y Liu
Apr 24, 2009·Journal of Cell Science·Morgan Huse
Sep 17, 2009·Immunological Reviews·Ian BaineFernando Macian
Dec 17, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Karnail SinghJörg J Goronzy
Mar 9, 2010·Current Opinion in Immunology·Peter S Kim, Rafi Ahmed
Apr 8, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matthias LeisegangElfriede Noessner
Jun 12, 2010·Immunological Reviews·Ilia VoskoboinikJoseph A Trapani
Dec 4, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Edwin J Vazquez-CintronAlan B Frey
Dec 9, 2010·The Journal of Biological Chemistry·Matthew J RieseGary A Koretzky
Feb 12, 2011·Blood·Balachandra K GorentlaXiao-Ping Zhong

❮ Previous
Next ❯

Citations

Apr 16, 2013·Critical Reviews in Immunology·Sruti Krishna, Xiaoping Zhong
Sep 14, 2016·Oncoimmunology·Frederik C HenrichAndreas Mackensen
Nov 2, 2016·Frontiers in Cell and Developmental Biology·Matthew J RieseSteven M Albelda
Mar 21, 2017·Frontiers in Cell and Developmental Biology·Elfriede Noessner
Mar 7, 2014·Journal of Pharmacological Sciences·Mitsue Ishisaka, Hideaki Hara
Mar 28, 2013·International Journal of Molecular Sciences·Rohan P Joshi, Gary A Koretzky
Mar 13, 2014·International Journal of Cancer. Journal International Du Cancer·Petra U PrinzElfriede Noessner
Nov 7, 2019·Genome Research·Maha AlriyamiConstantin Polychronakos
Nov 24, 2019·International Journal of Molecular Sciences·Poojitha SitaramMatthew J Riese
Jan 15, 2020·Nature Chemical Biology·Timothy B WareKu-Lung Hsu
Dec 18, 2019·Briefings in Functional Genomics·Guillermo Ureña-BailénMarkus Mezger
Jul 2, 2020·Clinical Science·Gianluca BaldanziMario Malerba
Mar 7, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lisa K SparyZsuzsanna Tabi
Sep 20, 2020·International Journal of Molecular Sciences·Fumio SakaneChiaki Murakami
Oct 3, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Helly VernitskyItamar Goldstein
Mar 25, 2018·Cancer Immunology, Immunotherapy : CII·Javier Arranz-NicolásAntonia Ávila-Flores
Sep 24, 2020·International Journal of Molecular Sciences·Jae Ang SimDongki Yang
May 24, 2019·International Journal of Molecular Sciences·Iris C SalaroglioChiara Riganti
Nov 29, 2020·Journal for Immunotherapy of Cancer·Javier Arranz-NicolásIsabel Merida
May 6, 2019·Cancer Immunology Research·Shaun M O'BrienSteven M Albelda
Jun 13, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edmund K MoonSteven M Albelda
Sep 2, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edmund K MoonSteven M Albelda
Apr 29, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jie LiSumin Kang
Oct 1, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Benjamin Purow
Nov 11, 2019·Advances in Biological Regulation·Javier Arranz-Nicolás, Isabel Mérida
Mar 6, 2021·Human Vaccines & Immunotherapeutics·Yuexin XuScott S Tykodi
Apr 11, 2021·Cancer Immunology, Immunotherapy : CII·Javier Arranz-NicolásIsabel Merida
Nov 21, 2017·Biochemistry·Rebecca L McCloudKu-Lung Hsu

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Biology: Molecular Imaging

Molecular imaging enables noninvasive imaging of key molecules that are crucial to tumor biology. Discover the latest research in molecular imaging in cancer biology in this feed.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.