Journal Article
. 2012 Sep; 209(11):2113-26.
doi: 10.1084/jem.20120532.

Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype

Daniel Hirschhorn-Cymerman 1 Sadna Budhu  Shigehisa Kitano  Cailian Liu  Feng Zhao  Hong Zhong  Alexander M Lesokhin  Francesca Avogadri-Connors  Jianda Yuan  Yanyun Li  Alan N Houghton  Taha Merghoub  Jedd D Wolchok  
  • PMID: 23008334
  •     64 References
  •     77 citations


Harnessing the adaptive immune response to treat malignancy is now a clinical reality. Several strategies are used to treat melanoma; however, very few result in a complete response. CD4(+) T cells are important and potent mediators of anti-tumor immunity and adoptive transfer of specific CD4(+) T cells can promote tumor regression in mice and patients. OX40, a costimulatory molecule expressed primarily on activated CD4(+) T cells, promotes and enhances anti-tumor immunity with limited success on large tumors in mice. We show that OX40 engagement, in the context of chemotherapy-induced lymphopenia, induces a novel CD4(+) T cell population characterized by the expression of the master regulator eomesodermin that leads to both terminal differentiation and central memory phenotype, with concomitant secretion of Th1 and Th2 cytokines. This subpopulation of CD4(+) T cells eradicates very advanced melanomas in mice, and an analogous population of human tumor-specific CD4(+) T cells can kill melanoma in an in vitro system. The potency of the therapy extends to support a bystander killing effect of antigen loss variants. Our results show that these uniquely programmed effector CD4(+) T cells have a distinctive phenotype with increased tumoricidal capability and support the use of immune modulation in reprogramming the phenotype of CD4(+) T cells.

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Signals that drive T follicular helper cell formation.
Louise M C Webb, Michelle A Linterman.
Immunology, 2017 Jun 20; 152(2). PMID: 28628194    Free PMC article.
An immunogenic personal neoantigen vaccine for patients with melanoma.
Patrick A Ott, Zhuting Hu, +37 authors, Catherine J Wu.
Nature, 2017 Jul 06; 547(7662). PMID: 28678778    Free PMC article.
Highly Cited.
Cancer: Precision T-cell therapy targets tumours.
Cornelis J M Melief.
Nature, 2017 Jul 06; 547(7662). PMID: 28678783
Fas Ligand-mediated cytotoxicity of CD4+ T cells during chronic retrovirus infection.
Anna Malyshkina, Elisabeth Littwitz-Salomon, +7 authors, Ulf Dittmer.
Sci Rep, 2017 Aug 12; 7(1). PMID: 28798348    Free PMC article.
Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3.
Yong-Chen Lu, Linda L Parker, +14 authors, Steven A Rosenberg.
J Clin Oncol, 2017 Aug 16; 35(29). PMID: 28809608    Free PMC article.
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Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.
Sadna Budhu, David A Schaer, +8 authors, Jedd D Wolchok.
Sci Signal, 2017 Aug 31; 10(494). PMID: 28851824    Free PMC article.
CD4 and CD8 T lymphocyte interplay in controlling tumor growth.
Dmitrij Ostroumov, Nora Fekete-Drimusz, +2 authors, Norman Woller.
Cell Mol Life Sci, 2017 Oct 17; 75(4). PMID: 29032503    Free PMC article.
Tumor-targeted costimulation with antibody-fusion proteins improves bispecific antibody-mediated immune response in presence of immunosuppressive factors.
Sabrina Sapski, Nadine Beha, Roland Kontermann, Dafne Müller.
Oncoimmunology, 2017 Dec 07; 6(12). PMID: 29209565    Free PMC article.
Tumor-infiltrating CD4+ T cells in patients with gastric cancer.
Long Yuan, Benling Xu, +8 authors, Quanli Gao.
Cancer Cell Int, 2017 Dec 08; 17. PMID: 29213216    Free PMC article.
Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells.
Ana Raykova, Paolo Carrega, +8 authors, Christian Münz.
Blood Adv, 2018 Jan 04; 1(27). PMID: 29296921    Free PMC article.
An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells.
Payal Mittal, Rebecca Abblett, +8 authors, Adam J Adler.
J Immunol, 2018 Jan 07; 200(4). PMID: 29305435    Free PMC article.
Citrullinated α-enolase is an effective target for anti-cancer immunity.
Katherine Cook, Ian Daniels, +6 authors, Victoria Brentville.
Oncoimmunology, 2018 Jan 09; 7(2). PMID: 29308319    Free PMC article.
Signaling by the Epstein-Barr virus LMP1 protein induces potent cytotoxic CD4+ and CD8+ T cell responses.
Il-Kyu Choi, Zhe Wang, +10 authors, Baochun Zhang.
Proc Natl Acad Sci U S A, 2018 Jan 10; 115(4). PMID: 29311309    Free PMC article.
Eradication of spontaneous malignancy by local immunotherapy.
Idit Sagiv-Barfi, Debra K Czerwinski, +4 authors, Ronald Levy.
Sci Transl Med, 2018 Feb 02; 10(426). PMID: 29386357    Free PMC article.
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Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.
Michael D Oberst, Catherine Augé, +19 authors, Scott A Hammond.
Mol Cancer Ther, 2018 Mar 17; 17(5). PMID: 29545330    Free PMC article.
Photochemical Internalization of Peptide Antigens Provides a Novel Strategy to Realize Therapeutic Cancer Vaccination.
Markus Haug, Gaute Brede, +7 authors, Øyvind Halaas.
Front Immunol, 2018 Apr 20; 9. PMID: 29670624    Free PMC article.
Foxo transcription factors in T cell biology and tumor immunity.
Chong T Luo, Ming O Li.
Semin Cancer Biol, 2018 Apr 24; 50. PMID: 29684436    Free PMC article.
IL-27 regulates the number, function and cytotoxic program of antiviral CD4 T cells and promotes cytomegalovirus persistence.
Ellen J Wehrens, Kurt A Wong, +3 authors, Elina I Zuniga.
PLoS One, 2018 Jul 26; 13(7). PMID: 30044874    Free PMC article.
Biological Consequences of MHC-II Expression by Tumor Cells in Cancer.
Margaret L Axelrod, Rebecca S Cook, Douglas B Johnson, Justin M Balko.
Clin Cancer Res, 2018 Nov 23; 25(8). PMID: 30463850    Free PMC article.
A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.
Douglas B Johnson, Wyatt J McDonnell, +30 authors, Justin M Balko.
Nat Med, 2019 Jul 25; 25(8). PMID: 31332390    Free PMC article.
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Striking a Balance-Cellular and Molecular Drivers of Memory T Cell Development and Responses to Chronic Stimulation.
Jennifer L Hope, Christopher J Stairiker, +2 authors, Linda M Bradley.
Front Immunol, 2019 Aug 06; 10. PMID: 31379821    Free PMC article.
High numbers of activated helper T cells are associated with better clinical outcome in early stage vulvar cancer, irrespective of HPV or p53 status.
Kim E Kortekaas, Saskia J Santegoets, +7 authors, Sjoerd H van der Burg.
J Immunother Cancer, 2019 Sep 05; 7(1). PMID: 31481117    Free PMC article.
Contributions of immune cell populations in the maintenance, progression, and therapeutic modalities of glioma.
Michael D Caponegro, Jeremy Tetsuo Miyauchi, Stella E Tsirka.
AIMS Allergy Immunol, 2018 Jan 01; 2(1). PMID: 32914058    Free PMC article.
Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.
Zhuting Hu, Donna E Leet, +38 authors, Patrick A Ott.
Nat Med, 2021 Jan 23; 27(3). PMID: 33479501    Free PMC article.
Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining.
Lingfeng Meng, Zijian Tian, +7 authors, Yuhui He.
Front Genet, 2021 Feb 16; 11. PMID: 33584797    Free PMC article.
Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer.
Amélie Cachot, Mariia Bilous, +22 authors, Camilla Jandus.
Sci Adv, 2021 Feb 28; 7(9). PMID: 33637530    Free PMC article.
Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity.
Zhi-Chun Ding, Huidong Shi, +11 authors, Gang Zhou.
Sci Immunol, 2020 Nov 01; 5(52). PMID: 33127608    Free PMC article.
MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It.
Elena Shklovskaya, Helen Rizos.
Int J Mol Sci, 2021 Jul 03; 22(13). PMID: 34201655    Free PMC article.
Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function.
Jayati Basu, Bernardo S Reis, +14 authors, Dietmar J Kappes.
Nat Immunol, 2021 Jul 28; 22(8). PMID: 34312548    Free PMC article.
Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma.
Juliette Paillet, Céleste Plantureux, +33 authors, Jonathan G Pol.
J Exp Med, 2021 Sep 09; 218(10). PMID: 34495298    Free PMC article.
Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy.
Myriam Ben Khelil, Yann Godet, +3 authors, Romain Loyon.
Cancers (Basel), 2022 Jan 12; 14(1). PMID: 35008422    Free PMC article.
Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.
Semir Beyaz, Charlie Chung, +30 authors, Ömer H Yilmaz.
Cell Stem Cell, 2021 Sep 17; 28(11). PMID: 34529935    Free PMC article.
Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox.
David Y Oh, Lawrence Fong.
Immunity, 2021 Dec 16; 54(12). PMID: 34910940    Free PMC article.
RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity.
Zhuo Zhang, Lin Luo, +14 authors, Eddy S Yang.
Nat Cancer, 2022 Feb 06; 2(10). PMID: 35121884    Free PMC article.
Neutrophil phenotypes and functions in cancer: A consensus statement.
Daniela F Quail, Borko Amulic, +22 authors, Paul Kubes.
J Exp Med, 2022 May 07; 219(6). PMID: 35522219    Free PMC article.