Journal Article
. 2013 Apr; 123(5):1999-2010.
doi: 10.1172/JCI63980.

CD40 ligation reverses T cell tolerance in acute myeloid leukemia

Long Zhang 1 Xiufen Chen  Xiao Liu  Douglas E Kline  Ryan M Teague  Thomas F Gajewski  Justin Kline  
Affiliations
  • PMID: 23619361
  •     41 References
  •     40 citations

Abstract

Spontaneous antigen-specific T cell responses can be generated in hosts harboring a variety of solid malignancies, but are subverted by immune evasion mechanisms active within the tumor microenvironment. In contrast to solid tumors, the mechanisms that regulate T cell activation versus tolerance to hematological malignancies have been underexplored. A murine acute myeloid leukemia (AML) model was used to investigate antigen-specific T cell responses against AML cells inoculated i.v. versus s.c. Robust antigen-specific T cell responses were generated against AML cells after s.c., but not i.v., inoculation. In fact, i.v. AML cell inoculation prevented functional T cell activation in response to subsequent s.c. AML cell challenge. T cell dysfunction was antigen specific and did not depend on Tregs or myeloid-derived suppressor cells (MDSCs). Antigen-specific TCR-Tg CD8+ T cells proliferated, but failed to accumulate, and expressed low levels of effector cytokines in hosts after i.v. AML induction, consistent with abortive T cell activation and peripheral tolerance. Administration of agonistic anti-CD40 Ab to activate host APCs enhanced accumulation of functional T cells and prolonged survival. Our results suggest that antigen-specific T cell tolerance is a potent immune evasion mechanism in hosts with AML that can be reversed in vivo after CD40 engagement.

CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
Gregory L Beatty, Elena G Chiorean, +10 authors, Robert H Vonderheide.
Science, 2011 Mar 26; 331(6024). PMID: 21436454    Free PMC article.
Highly Cited.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
Mark S Diamond, Michelle Kinder, +9 authors, Robert D Schreiber.
J Exp Med, 2011 Sep 21; 208(10). PMID: 21930769    Free PMC article.
Highly Cited.
Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.
Qing Zhou, Meghan E Munger, +11 authors, Bruce R Blazar.
Blood, 2010 Jun 24; 116(14). PMID: 20570856    Free PMC article.
Highly Cited.
Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors.
François Ghiringhelli, Lionel Apetoh, +23 authors, Laurence Zitvogel.
Nat Med, 2009 Sep 22; 15(10). PMID: 19767732
Highly Cited.
Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells.
Mercedes B Fuertes, Aalok K Kacha, +4 authors, Thomas F Gajewski.
J Exp Med, 2011 Sep 21; 208(10). PMID: 21930765    Free PMC article.
Highly Cited.
Induction of antigen-specific T cell anergy: An early event in the course of tumor progression.
K Staveley-O'Carroll, E Sotomayor, +5 authors, H Levitsky.
Proc Natl Acad Sci U S A, 1998 Mar 14; 95(3). PMID: 9448305    Free PMC article.
Highly Cited.
Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells.
Andrew J Rech, Robert H Vonderheide.
Ann N Y Acad Sci, 2009 Sep 23; 1174. PMID: 19769742
Highly Cited. Review.
LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
Joseph F Grosso, Cristin C Kelleher, +10 authors, Charles G Drake.
J Clin Invest, 2007 Oct 13; 117(11). PMID: 17932562    Free PMC article.
Highly Cited.
Uncoupling of proliferative potential and gain of effector function by CD8(+) T cells responding to self-antigens.
Javier Hernández, Sandra Aung, Kristi Marquardt, Linda A Sherman.
J Exp Med, 2002 Aug 07; 196(3). PMID: 12163561    Free PMC article.
PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model.
Long Zhang, Thomas F Gajewski, Justin Kline.
Blood, 2009 May 07; 114(8). PMID: 19417208    Free PMC article.
Highly Cited.
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors.
Ryan M Teague, Blythe D Sather, +8 authors, Philip D Greenberg.
Nat Med, 2006 Feb 14; 12(3). PMID: 16474399
Mechanisms of transplant tolerance induction using costimulatory blockade.
Thomas Wekerle, Josef Kurtz, +2 authors, Megan Sykes.
Curr Opin Immunol, 2002 Aug 17; 14(5). PMID: 12183158
Review.
CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens.
Kenichi Asano, Ami Nabeyama, +6 authors, Masato Tanaka.
Immunity, 2011 Jan 05; 34(1). PMID: 21194983
Highly Cited.
Science gone translational: the OX40 agonist story.
Andrew D Weinberg, Nicholas P Morris, +2 authors, Brendan D Curti.
Immunol Rev, 2011 Oct 25; 244(1). PMID: 22017441    Free PMC article.
Review.
Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo.
William L Redmond, Michael J Gough, Andrew D Weinberg.
Eur J Immunol, 2009 Aug 13; 39(8). PMID: 19672905    Free PMC article.
Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma.
Justin Kline, Ian E Brown, +5 authors, Thomas F Gajewski.
Clin Cancer Res, 2008 May 17; 14(10). PMID: 18483384
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
Catherine Uyttenhove, Luc Pilotte, +5 authors, Benoît J Van den Eynde.
Nat Med, 2003 Sep 23; 9(10). PMID: 14502282
Highly Cited.
Uric acid promotes tumor immune rejection.
De-En Hu, Alistair M Moore, Lindy L Thomsen, Kevin M Brindle.
Cancer Res, 2004 Aug 04; 64(15). PMID: 15289304
Tumor antigens.
J L Urban, H Schreiber.
Annu Rev Immunol, 1992 Jan 01; 10. PMID: 1590998
Review.
Bcl-XL and Bcl-2 repress a common pathway of cell death.
D T Chao, G P Linette, +3 authors, S J Korsmeyer.
J Exp Med, 1995 Sep 01; 182(3). PMID: 7650488    Free PMC article.
Highly Cited.
Calreticulin exposure dictates the immunogenicity of cancer cell death.
Michel Obeid, Antoine Tesniere, +14 authors, Guido Kroemer.
Nat Med, 2006 Dec 26; 13(1). PMID: 17187072
Highly Cited.
Immune resistance orchestrated by the tumor microenvironment.
Thomas F Gajewski, Yuru Meng, +4 authors, Helena Harlin.
Immunol Rev, 2006 Sep 16; 213. PMID: 16972901
Highly Cited. Review.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy.
L Diehl, A T den Boer, +5 authors, R E Toes.
Nat Med, 1999 Jul 08; 5(7). PMID: 10395322
Highly Cited.
Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression.
E M Sotomayor, I Borrello, +4 authors, H I Levitsky.
Blood, 2001 Aug 09; 98(4). PMID: 11493453
Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells.
Michael T Spiotto, Ping Yu, +5 authors, Hans Schreiber.
Immunity, 2002 Dec 14; 17(6). PMID: 12479820
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.
Robert H Vonderheide, Keith T Flaherty, +12 authors, Scott J Antonia.
J Clin Oncol, 2007 Mar 01; 25(7). PMID: 17327609
Highly Cited.
LAG-3 in Cancer Immunotherapy.
Monica V Goldberg, Charles G Drake.
Curr Top Microbiol Immunol, 2010 Nov 19; 344. PMID: 21086108    Free PMC article.
Review.
Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.
Jeong M Kim, Jeffrey P Rasmussen, Alexander Y Rudensky.
Nat Immunol, 2006 Dec 01; 8(2). PMID: 17136045
Highly Cited.
In vivo ligation of CD40 enhances priming against the endogenous tumor antigen and promotes CD8+ T cell effector function in SV40 T antigen transgenic mice.
Kevin Staveley-O'Carroll, Todd D Schell, +4 authors, Satvir S Tevethia.
J Immunol, 2003 Jul 09; 171(2). PMID: 12847236
Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
Lionel Apetoh, François Ghiringhelli, +25 authors, Laurence Zitvogel.
Nat Med, 2007 Aug 21; 13(9). PMID: 17704786
Highly Cited.
Phenotypic and functional analysis of CD8(+) T cells undergoing peripheral deletion in response to cross-presentation of self-antigen.
J Hernandez, S Aung, W L Redmond, L A Sherman.
J Exp Med, 2001 Sep 19; 194(6). PMID: 11560988    Free PMC article.
Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40.
E M Sotomayor, I Borrello, +6 authors, H I Levitsky.
Nat Med, 1999 Jul 08; 5(7). PMID: 10395323
Highly Cited.
Regulatory T cells, tumour immunity and immunotherapy.
Weiping Zou.
Nat Rev Immunol, 2006 Mar 25; 6(4). PMID: 16557261
Highly Cited. Review.
Distinct requirements for deletion versus anergy during CD8 T cell peripheral tolerance in vivo.
William L Redmond, Boris C Marincek, Linda A Sherman.
J Immunol, 2005 Feb 09; 174(4). PMID: 15699134
CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help.
R R French, H T Chan, A L Tutt, M J Glennie.
Nat Med, 1999 May 06; 5(5). PMID: 10229232
Highly Cited.
CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function.
Claes Ohlén, Michael Kalos, +8 authors, Philip D Greenberg.
J Exp Med, 2002 Jun 05; 195(11). PMID: 12045239    Free PMC article.
The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo.
Tomonori Iyoda, Susumu Shimoyama, +6 authors, Kayo Inaba.
J Exp Med, 2002 May 22; 195(10). PMID: 12021309    Free PMC article.
Highly Cited.
Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity.
Suzanne Ostrand-Rosenberg.
Cancer Immunol Immunother, 2010 Apr 24; 59(10). PMID: 20414655    Free PMC article.
Highly Cited. Review.
In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance.
E M Sotomayor, I Borrello, +2 authors, H I Levitsky.
Proc Natl Acad Sci U S A, 1999 Sep 29; 96(20). PMID: 10500201    Free PMC article.
Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity.
Dewan Md Sakib Hossain, Cedric Dos Santos, +11 authors, Marcin Kortylewski.
Blood, 2013 Oct 31; 123(1). PMID: 24169824    Free PMC article.
Peripheral T-cell tolerance in hosts with acute myeloid leukemia.
Xiufen Chen, Douglas E Kline, Justin Kline.
Oncoimmunology, 2013 Nov 02; 2(8). PMID: 24179704    Free PMC article.
The targeting of immunosuppressive mechanisms in hematological malignancies.
M H Andersen.
Leukemia, 2014 Apr 03; 28(9). PMID: 24691076
Review.
Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.
Ping-Chih Ho, Katrina M Meeth, +3 authors, Susan M Kaech.
Cancer Res, 2014 Apr 17; 74(12). PMID: 24736544    Free PMC article.
Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia.
Valentina Folgiero, Bianca M Goffredo, +12 authors, Sergio Rutella.
Oncotarget, 2014 Jun 07; 5(8). PMID: 24903009    Free PMC article.
Targeting CD8+ T-cell tolerance for cancer immunotherapy.
Stephanie R Jackson, Jinyun Yuan, Ryan M Teague.
Immunotherapy, 2014 Oct 08; 6(7). PMID: 25290416    Free PMC article.
Review.
Myeloid-derived suppressor cells as therapeutic target in hematological malignancies.
Kim De Veirman, Els Van Valckenborgh, +6 authors, Jo A Van Ginderachter.
Front Oncol, 2014 Dec 30; 4. PMID: 25538893    Free PMC article.
Review.
Targeting the innate immune system as immunotherapy for acute myeloid leukemia.
Emily Curran, Leticia Corrales, Justin Kline.
Front Oncol, 2015 Apr 29; 5. PMID: 25914882    Free PMC article.
Review.
Immunomodulatory Drugs: Immune Checkpoint Agents in Acute Leukemia.
Hanna A Knaus, Christopher G Kanakry, Leo Luznik, Ivana Gojo.
Curr Drug Targets, 2015 May 20; 18(3). PMID: 25981611    Free PMC article.
Review.
An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells.
Kana Hasegawa, Satomi Tanaka, +12 authors, Naoki Hosen.
PLoS One, 2015 Dec 15; 10(12). PMID: 26658107    Free PMC article.
Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape.
Sanmay Bandyopadhyay, Thomas J Quinn, +5 authors, Chandan Guha.
J Immunol, 2016 Jan 13; 196(4). PMID: 26755821    Free PMC article.
Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia.
Qifang Zhang, Dewan Md Sakib Hossain, +13 authors, Marcin Kortylewski.
Blood, 2016 Jan 23; 127(13). PMID: 26796361    Free PMC article.
STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia.
Emily Curran, Xiufen Chen, +5 authors, Justin Kline.
Cell Rep, 2016 Jun 07; 15(11). PMID: 27264175    Free PMC article.
Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia.
Lei Qin, Donye Dominguez, +7 authors, Bin Zhang.
Oncotarget, 2016 Aug 16; 7(38). PMID: 27517629    Free PMC article.
Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia.
Xiufen Chen, Dominick Fosco, Douglas E Kline, Justin Kline.
Oncoimmunology, 2017 May 17; 6(4). PMID: 28507789    Free PMC article.
Mechanisms of Immune Tolerance in Leukemia and Lymphoma.
Emily K Curran, James Godfrey, Justin Kline.
Trends Immunol, 2017 May 18; 38(7). PMID: 28511816    Free PMC article.
Review.
Natural Killer Defective Maturation Is Associated with Adverse Clinical Outcome in Patients with Acute Myeloid Leukemia.
Anne-Sophie Chretien, Cyril Fauriat, +19 authors, Daniel Olive.
Front Immunol, 2017 Jun 15; 8. PMID: 28611767    Free PMC article.
The emerging role of immune checkpoint based approaches in AML and MDS.
Prajwal Boddu, Hagop Kantarjian, +3 authors, Naval Daver.
Leuk Lymphoma, 2017 Jul 07; 59(4). PMID: 28679300    Free PMC article.
Review.
Intratumoral CD8+ T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor Immunity.
Brendan L Horton, Jason B Williams, +2 authors, Thomas F Gajewski.
Cancer Immunol Res, 2017 Nov 04; 6(1). PMID: 29097422    Free PMC article.
Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy.
Hanna A Knaus, Sofia Berglund, +9 authors, Ivana Gojo.
JCI Insight, 2018 Nov 06; 3(21). PMID: 30385732    Free PMC article.
CD33/CD3-bispecific T-cell engaging (BiTE®) antibody construct targets monocytic AML myeloid-derived suppressor cells.
Regina Jitschin, Domenica Saul, +7 authors, Dimitrios Mougiakakos.
J Immunother Cancer, 2018 Nov 07; 6(1). PMID: 30396365    Free PMC article.
IL12 Abrogates Calcineurin-Dependent Immune Evasion during Leukemia Progression.
Jennifer L Rabe, Lori Gardner, +14 authors, Christopher C Porter.
Cancer Res, 2019 May 31; 79(14). PMID: 31142509    Free PMC article.
The ST2/Interleukin-33 Axis in Hematologic Malignancies: The IL-33 Paradox.
Alessandro Allegra, Vanessa Innao, +4 authors, Sebastiano Gangemi.
Int J Mol Sci, 2019 Oct 28; 20(20). PMID: 31652497    Free PMC article.
Review.
Immunotherapy for acute myeloid leukemia: from allogeneic stem cell transplant to novel therapeutics.
David A Knorr, Aaron D Goldberg, Eytan M Stein, Martin S Tallman.
Leuk Lymphoma, 2019 Jul 25; 60(14). PMID: 31335250    Free PMC article.
Review.
Perihematomal Edema After Intracerebral Hemorrhage in Patients With Active Malignancy.
Aaron M Gusdon, Paul A Nyquist, +6 authors, Rachna Malani.
Stroke, 2019 Nov 21; 51(1). PMID: 31744426    Free PMC article.
CD8α+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates.
Douglas E Kline, Brendan W MacNabb, +3 authors, Justin Kline.
J Immunol, 2018 Nov 14; 201(12). PMID: 30420437    Free PMC article.
B7-Positive and B7-Negative Acute Myeloid Leukemias Display Distinct T Cell Maturation Profiles, Immune Checkpoint Receptor Expression, and European Leukemia Net Risk Profiles.
Ion Antohe, Angela Dǎscǎlescu, +6 authors, Petru Cianga.
Front Oncol, 2020 Apr 02; 10. PMID: 32231996    Free PMC article.
Immune escape and immunotherapy of acute myeloid leukemia.
Luca Vago, Ivana Gojo.
J Clin Invest, 2020 Apr 03; 130(4). PMID: 32235097    Free PMC article.
Review.
mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment.
Antonio Vella, Elisabetta D'Aversa, +17 authors, Valentino Bezzerri.
Cancers (Basel), 2020 Mar 11; 12(3). PMID: 32150944    Free PMC article.
Alterations of T-cell-mediated immunity in acute myeloid leukemia.
Zhuoyan Li, Mary Philip, P Brent Ferrell.
Oncogene, 2020 Mar 05; 39(18). PMID: 32127646    Free PMC article.
Review.
cGAS-STING pathway in oncogenesis and cancer therapeutics.
Brandon Yi Da Hoong, Yunn Hwen Gan, Haiyan Liu, Ee Sin Chen.
Oncotarget, 2020 Aug 11; 11(30). PMID: 32774773    Free PMC article.
Review.
Fifty Shades of Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm.
Michelle L Miller, Anita S Chong, Maria-Luisa Alegre.
Curr Transplant Rep, 2017 Dec 01; 4(4). PMID: 31098340    Free PMC article.
An effective peptide vaccine strategy circumventing clonal MHC heterogeneity of murine myeloid leukaemia.
A-Ri Shin, Sang-Eun Lee, +3 authors, Tai-Gyu Kim.
Br J Cancer, 2020 Jul 01; 123(6). PMID: 32595211    Free PMC article.
Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions.
Chiara Montironi, Cristina Muñoz-Pinedo, Eric Eldering.
Cancers (Basel), 2021 Jan 21; 13(2). PMID: 33466674    Free PMC article.
Review.
Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment.
Rongqun Guo, Mengdie Lü, +16 authors, Zhongxing Jiang.
Biomark Res, 2021 Mar 03; 9(1). PMID: 33648605    Free PMC article.
Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?
Laura Jimbu, Oana Mesaros, +5 authors, Mihnea Zdrenghea.
Pharmaceuticals (Basel), 2021 Apr 04; 14(4). PMID: 33804850    Free PMC article.
Review.
CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies.
Timothy N J Bullock.
Cell Mol Immunol, 2021 Jul 21; 19(1). PMID: 34282297    Free PMC article.
Review.
Acute myeloid leukemia cell membrane-coated nanoparticles for cancer vaccination immunotherapy.
Daniel T Johnson, Jiarong Zhou, +7 authors, Dong-Er Zhang.
Leukemia, 2021 Dec 01; 36(4). PMID: 34845316    Free PMC article.
Divergent fates of antigen-specific CD8+ T cell clones in mice with acute leukemia.
Xiufen Chen, Brendan W MacNabb, +2 authors, Justin Kline.
Cell Rep, 2021 Nov 11; 37(6). PMID: 34758311    Free PMC article.
LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma.
Yongcheng Su, Beibei Xu, +3 authors, Tianhui Hu.
Front Immunol, 2022 Mar 12; 13. PMID: 35273591    Free PMC article.