Review
. 2022 Jan; 14(1):.
doi: 10.3390/cancers14010260.

Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy

Myriam Ben Khelil 1 Yann Godet 1 Syrine Abdeljaoued 1 Christophe Borg 1 Olivier Adotévi 1 Romain Loyon 1 
Affiliations
  • PMID: 35008422
  •     241 References
  •     1 citations

Abstract

Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can either suppress or promote the antitumor cytotoxic CD8+ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4+ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4+ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4+ T cells to control tumor progression and prevent recurrence in patients.

Keywords: CD4+ T cells; adoptive cell transfer; cancer immunotherapy; cancer vaccine; immune checkpoint inhibitors.

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CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors.
Markus Chmielewski, Hinrich Abken.
Cell Rep, 2017 Dec 16; 21(11). PMID: 29241547
Highly Cited.
IL-4 attenuates Th1-associated chemokine expression and Th1 trafficking to inflamed tissues and limits pathogen clearance.
Christopher A Lazarski, Jill Ford, +2 authors, Deborah J Fowell.
PLoS One, 2013 Aug 31; 8(8). PMID: 23991011    Free PMC article.
Radiotherapy induces responses of lung cancer to CTLA-4 blockade.
Silvia C Formenti, Nils-Petter Rudqvist, +15 authors, Sandra Demaria.
Nat Med, 2018 Nov 07; 24(12). PMID: 30397353    Free PMC article.
Highly Cited.
Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4+ T cells.
Jan A Rath, Gagan Bajwa, +15 authors, Caroline Arber.
Sci Adv, 2020 Sep 15; 6(27). PMID: 32923584    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.
Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts.
Jessica Hartmann, Martina Schüßler-Lenz, Attilio Bondanza, Christian J Buchholz.
EMBO Mol Med, 2017 Aug 03; 9(9). PMID: 28765140    Free PMC article.
Highly Cited. Review.
High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients.
Daniel M Frey, Raoul A Droeser, +7 authors, Luigi Tornillo.
Int J Cancer, 2009 Oct 27; 126(11). PMID: 19856313
Highly Cited.
IL-17A promotes immune cell recruitment in human esophageal cancers and the infiltrating dendritic cells represent a positive prognostic marker for patient survival.
Lin Lu, Ke Pan, +10 authors, Jian-Chuan Xia.
J Immunother, 2013 Sep 03; 36(8). PMID: 23994890
CAR T cell immunotherapy for human cancer.
Carl H June, Roddy S O'Connor, +2 authors, Michael C Milone.
Science, 2018 Mar 24; 359(6382). PMID: 29567707
Highly Cited. Review.
HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ.
Anupama Sharma, Ursula Koldovsky, +10 authors, Brian J Czerniecki.
Cancer, 2012 Jan 19; 118(17). PMID: 22252842    Free PMC article.
Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients.
Sharon A Oldford, J Desmond Robb, +3 authors, Sheila Drover.
Int Immunol, 2006 Sep 22; 18(11). PMID: 16987935
Granule exocytosis, and not the fas/fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4(+) as well as CD8(+) cytotoxic T lymphocytes in humans.
M Yasukawa, H Ohminami, +3 authors, S Fujita.
Blood, 2000 Mar 25; 95(7). PMID: 10733506
Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4⁺ T cell immunity.
Bernardo Sgarbi Reis, Aneta Rogoz, +2 authors, Daniel Mucida.
Nat Immunol, 2013 Jan 22; 14(3). PMID: 23334789    Free PMC article.
Highly Cited.
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Douglas B Johnson, Monica V Estrada, +18 authors, Justin M Balko.
Nat Commun, 2016 Jan 30; 7. PMID: 26822383    Free PMC article.
Highly Cited.
T follicular helper cell heterogeneity: Time, space, and function.
Wenzhi Song, Joe Craft.
Immunol Rev, 2019 Mar 16; 288(1). PMID: 30874350    Free PMC article.
Highly Cited. Review.
IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells.
Steven A Rosenberg, Claude Sportès, +10 authors, Ronald E Gress.
J Immunother, 2006 May 16; 29(3). PMID: 16699374    Free PMC article.
Highly Cited.
CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination.
Tomasz Ahrends, Nikolina Bąbała, +3 authors, Jannie Borst.
Cancer Res, 2016 Mar 30; 76(10). PMID: 27020860
Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers-Response.
Anu Sharma, Sumit K Subudhi, +5 authors, Padmanee Sharma.
Clin Cancer Res, 2019 Jun 05; 25(11). PMID: 31160495    Free PMC article.
Tumor-infiltrating FoxP3+ Tregs predict favorable outcome in colorectal cancer patients: A meta-analysis.
Guoming Hu, Zhi'an Li, Shimin Wang.
Oncotarget, 2017 Nov 02; 8(43). PMID: 29088871    Free PMC article.
Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.
Eric Tran, Simon Turcotte, +10 authors, Steven A Rosenberg.
Science, 2014 May 09; 344(6184). PMID: 24812403    Free PMC article.
Highly Cited.
CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.
Arata Takeuchi, Mohamed El Sherif Gadelhaq Badr, +11 authors, Takashi Saito.
J Exp Med, 2015 Dec 24; 213(1). PMID: 26694968    Free PMC article.
Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma.
Luis Vence, A Karolina Palucka, +4 authors, Hideki Ueno.
Proc Natl Acad Sci U S A, 2007 Dec 21; 104(52). PMID: 18093940    Free PMC article.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Tyler J Curiel, George Coukos, +18 authors, Weiping Zou.
Nat Med, 2004 Aug 24; 10(9). PMID: 15322536
Highly Cited.
The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma.
Lin Lv, Ke Pan, +7 authors, Jian-chuan Xia.
PLoS One, 2011 Apr 13; 6(3). PMID: 21483813    Free PMC article.
Th17 response in patients with cervical cancer.
Jayra Juliana Paiva Alves, Thales Allyrio Araújo De Medeiros Fernandes, +5 authors, José Veríssimo Fernandes.
Oncol Lett, 2018 Nov 09; 16(5). PMID: 30405758    Free PMC article.
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Higher levels of GATA3 predict better survival in women with breast cancer.
Nam K Yoon, Erin L Maresh, +8 authors, Lee Goodglick.
Hum Pathol, 2010 Nov 17; 41(12). PMID: 21078439    Free PMC article.
CD39 Identifies the CD4+ Tumor-Specific T-cell Population in Human Cancer.
Kim E Kortekaas, Saskia J Santegoets, +7 authors, Sjoerd H van der Burg.
Cancer Immunol Res, 2020 Aug 08; 8(10). PMID: 32759363
Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.
Sen Liu, Qiuyang Zhang, +16 authors, Zongbing You.
Oncotarget, 2016 Feb 13; 7(12). PMID: 26871944    Free PMC article.
Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype.
Zhi-Chun Ding, Bruce R Blazar, +2 authors, Gang Zhou.
Blood, 2010 Feb 02; 115(12). PMID: 20118405    Free PMC article.
Continuous requirement for the TCR in regulatory T cell function.
Andrew G Levine, Aaron Arvey, Wei Jin, Alexander Y Rudensky.
Nat Immunol, 2014 Sep 30; 15(11). PMID: 25263123    Free PMC article.
Highly Cited.
The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases.
David Klatzmann, Abul K Abbas.
Nat Rev Immunol, 2015 Apr 18; 15(5). PMID: 25882245
Highly Cited. Review.
Memory type 2 helper T cells induce long-lasting antitumor immunity by activating natural killer cells.
Masayuki Kitajima, Toshihiro Ito, +8 authors, Toshinori Nakayama.
Cancer Res, 2011 Jun 08; 71(14). PMID: 21646476
Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model.
Pablo Matar, Viviana R Rozados, Silvia I Gervasoni, Graciela O Scharovsky.
Cancer Immunol Immunother, 2002 Jan 25; 50(11). PMID: 11807622
Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin's lymphoma.
M Fischer, M Bijman, +6 authors, G Nilsson.
Leukemia, 2003 Oct 17; 17(12). PMID: 14562126
The Next Decade of Immune Checkpoint Therapy.
Padmanee Sharma, Bilal A Siddiqui, +5 authors, James P Allison.
Cancer Discov, 2021 Apr 04; 11(4). PMID: 33811120
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Therapy with CD4+CD25+ T regulatory cells - should we be afraid of cancer?
Mateusz Gliwiński, Magdalena Piotrowska, +2 authors, Piotr Trzonkowski.
Contemp Oncol (Pozn), 2019 May 08; 23(1). PMID: 31061630    Free PMC article.
Review.
Cytotoxic CD4+ T-cells during HIV infection: Targets or weapons?
Alexandra Sanchez-Martinez, Federico Perdomo-Celis, +2 authors, Paula A Velilla.
J Clin Virol, 2019 Aug 25; 119. PMID: 31445411
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Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes.
Charlie T Garnett, Claudia Palena, +4 authors, James W Hodge.
Cancer Res, 2004 Nov 03; 64(21). PMID: 15520206
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Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma.
Stephen J Schuster, Michael R Bishop, +22 authors, JULIET Investigators.
N Engl J Med, 2018 Dec 07; 380(1). PMID: 30501490
Highly Cited.
Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy.
Elodie Renaude, Marie Kroemer, +4 authors, Olivier Adotévi.
Front Immunol, 2021 Jul 16; 12. PMID: 34262562    Free PMC article.
Review.
Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering an In Situ Inflammatory Immune Response.
Kristina Berg Lorvik, Clara Hammarström, +5 authors, Alexandre Corthay.
Cancer Res, 2016 Sep 17; 76(23). PMID: 27634753
IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells.
Donggou He, Hui Li, +4 authors, Hui Xu.
J Immunol, 2010 Feb 02; 184(5). PMID: 20118280    Free PMC article.
Highly Cited.
Intratumoral expression of IL-17 and its prognostic role in gastric adenocarcinoma patients.
Ju-gao Chen, Jian-chuan Xia, +16 authors, Qiao Li.
Int J Biol Sci, 2011 Jan 15; 7(1). PMID: 21234303    Free PMC article.
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A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone.
S A Rosenberg, M T Lotze, +7 authors, J T Rubin.
N Engl J Med, 1987 Apr 09; 316(15). PMID: 3493432
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Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy.
Shiping Jiao, Sumit K Subudhi, +4 authors, Padmanee Sharma.
Cell, 2019 Nov 16; 179(5). PMID: 31730856
Highly Cited.
Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
Rita Cabrita, Martin Lauss, +22 authors, Göran Jönsson.
Nature, 2020 Jan 17; 577(7791). PMID: 31942071
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Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer.
Marie Tosolini, Amos Kirilovsky, +8 authors, Jérôme Galon.
Cancer Res, 2011 Feb 10; 71(4). PMID: 21303976
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Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial.
Paal Fr Brunsvig, Jon Amund Kyte, +6 authors, Steinar Aamdal.
Clin Cancer Res, 2011 Sep 16; 17(21). PMID: 21918169
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
T-bet promotes potent antitumor activity of CD4+ CAR T cells.
Albert T Gacerez, Charles L Sentman.
Cancer Gene Ther, 2018 Mar 09; 25(5-6). PMID: 29515240    Free PMC article.
Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment.
Oladapo O Yeku, Terence J Purdon, +2 authors, Renier J Brentjens.
Sci Rep, 2017 Sep 07; 7(1). PMID: 28874817    Free PMC article.
Highly Cited.
Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing.
Xinyi Guo, Yuanyuan Zhang, +16 authors, Zemin Zhang.
Nat Med, 2018 Jun 27; 24(7). PMID: 29942094
Highly Cited.
Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling.
In Ah Park, Seong-Hye Hwang, +7 authors, Hee Jin Lee.
PLoS One, 2017 Aug 18; 12(8). PMID: 28817603    Free PMC article.
Effect of gamma interferon on HLA class-I and -II transcription and protein expression in human breast adenocarcinoma cell lines.
N Jabrane-Ferrat, A Faille, +3 authors, F Calvo.
Int J Cancer, 1990 Jun 15; 45(6). PMID: 2112515
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer.
Ninke Leffers, Marloes J M Gooden, +7 authors, Hans W Nijman.
Cancer Immunol Immunother, 2008 Sep 16; 58(3). PMID: 18791714
Highly Cited.
Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer.
Yuanyuan Zhang, Hongyan Chen, +17 authors, Zhihua Liu.
Cancer Cell, 2021 Oct 16; 39(12). PMID: 34653365
Phase 1 study of stereotactic body radiotherapy and interleukin-2--tumor and immunological responses.
Steven K Seung, Brendan D Curti, +8 authors, Walter J Urba.
Sci Transl Med, 2012 Jun 08; 4(137). PMID: 22674552
Highly Cited.
Telomerase and CD4 T Cell Immunity in Cancer.
Magalie Dosset, Andrea Castro, Hannah Carter, Maurizio Zanetti.
Cancers (Basel), 2020 Jul 08; 12(6). PMID: 32630460    Free PMC article.
Review.
Relative expression levels of Th1 and Th2 cytokine mRNA are independent prognostic factors in patients with ovarian cancer.
Tomoyo Kusuda, Kazushi Shigemasa, +3 authors, Koso Ohama.
Oncol Rep, 2005 May 05; 13(6). PMID: 15870936
Adoptive transfer of tumor-primed, in vitro-activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response.
Li-Xin Wang, Suyu Shu, Mary L Disis, Gregory E Plautz.
Blood, 2007 Feb 08; 109(11). PMID: 17284532    Free PMC article.
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma.
Scott J Rodig, Daniel Gusenleitner, +13 authors, F Stephen Hodi.
Sci Transl Med, 2018 Jul 20; 10(450). PMID: 30021886
Highly Cited.
Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells.
Blanca Homet Moreno, Jesse M Zaretsky, +11 authors, Antoni Ribas.
Cancer Immunol Res, 2016 Sep 04; 4(10). PMID: 27589875    Free PMC article.
Plasticity of CD4+ T cell lineage differentiation.
Liang Zhou, Mark M W Chong, Dan R Littman.
Immunity, 2009 May 26; 30(5). PMID: 19464987
Highly Cited. Review.
Abscopal effect of radiation in papillary adenocarcinoma.
G Ehlers, M Fridman.
Br J Radiol, 1973 Mar 01; 46(543). PMID: 4706791
Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts.
Sergio A Quezada, Tyler R Simpson, +9 authors, James P Allison.
J Exp Med, 2010 Feb 17; 207(3). PMID: 20156971    Free PMC article.
Highly Cited.
Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression.
Jian Li, George Ka-Kit Lau, +7 authors, Xin-yuan Guan.
PLoS One, 2011 Jul 16; 6(7). PMID: 21760911    Free PMC article.
Neoantigen landscape dynamics during human melanoma-T cell interactions.
Els M E Verdegaal, Noel F C C de Miranda, +11 authors, Sjoerd H van der Burg.
Nature, 2016 Jun 29; 536(7614). PMID: 27350335
Highly Cited.
Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection.
Ester M M van Leeuwen, Ester B M Remmerswaal, +4 authors, Ineke J M ten Berge.
J Immunol, 2004 Jul 22; 173(3). PMID: 15265915
Inducible apoptosis as a safety switch for adoptive cell therapy.
Antonio Di Stasi, Siok-Keen Tey, +17 authors, Malcolm K Brenner.
N Engl J Med, 2011 Nov 04; 365(18). PMID: 22047558    Free PMC article.
Highly Cited.
Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer.
Ylia Salazar, Xiang Zheng, +20 authors, Rajkumar Savai.
J Clin Invest, 2020 Apr 02; 130(7). PMID: 32229721    Free PMC article.
Is preexisting antitumor CD4 T cell response indispensable for the chemotherapy induced immune regression of cancer?
Yann Godet, Magalie Dosset, Christophe Borg, Olivier Adotevi.
Oncoimmunology, 2012 Dec 25; 1(9). PMID: 23264913    Free PMC article.
Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.
Rahul Purwar, Christoph Schlapbach, +9 authors, Thomas S Kupper.
Nat Med, 2012 Jul 10; 18(8). PMID: 22772464    Free PMC article.
Highly Cited.
Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade.
Imran G House, Peter Savas, +17 authors, Paul A Beavis.
Clin Cancer Res, 2019 Oct 23; 26(2). PMID: 31636098
Th9 cells: a novel CD4 T-cell subset in the immune war against cancer.
Frédérique Végran, Lionel Apetoh, François Ghiringhelli.
Cancer Res, 2015 Jan 16; 75(3). PMID: 25589348
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Cytotoxic CD4 T cells in viral hepatitis.
N Aslan, C Yurdaydin, +11 authors, H Wedemeyer.
J Viral Hepat, 2006 Aug 12; 13(8). PMID: 16901280
Tumor Immunology and Tumor Evolution: Intertwined Histories.
Jérôme Galon, Daniela Bruni.
Immunity, 2020 Jan 16; 52(1). PMID: 31940273
Review.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment.
Young-Dae Kim, Sang-Min Park, +5 authors, Joong Myung Cho.
J Cancer, 2020 May 06; 11(14). PMID: 32368288    Free PMC article.
Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.
Takuro Saito, Hiroyoshi Nishikawa, +19 authors, Shimon Sakaguchi.
Nat Med, 2016 Apr 26; 22(6). PMID: 27111280
Highly Cited.
Regulatory T cells in tumor immunity.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Int J Cancer, 2010 Jun 03; 127(4). PMID: 20518016
Highly Cited. Review.
Lineage tracking reveals dynamic relationships of T cells in colorectal cancer.
Lei Zhang, Xin Yu, +17 authors, Zemin Zhang.
Nature, 2018 Nov 28; 564(7735). PMID: 30479382
Highly Cited.
Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer.
Sidharth V Puram, Itay Tirosh, +16 authors, Bradley E Bernstein.
Cell, 2017 Dec 05; 171(7). PMID: 29198524    Free PMC article.
Highly Cited.
In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer.
Franck Pagès, Amos Kirilovsky, +12 authors, Jérôme Galon.
J Clin Oncol, 2009 Oct 28; 27(35). PMID: 19858404
Highly Cited.
Chimeric antigen receptor T-cell therapy - assessment and management of toxicities.
Sattva S Neelapu, Sudhakar Tummala, +16 authors, Elizabeth J Shpall.
Nat Rev Clin Oncol, 2017 Sep 20; 15(1). PMID: 28925994    Free PMC article.
Highly Cited. Review.
Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses.
Can Cui, Jiawei Wang, +13 authors, Nikhil S Joshi.
Cell, 2021 Dec 02; 184(25). PMID: 34852236    Free PMC article.
Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy.
Deborah M Brown.
Cell Immunol, 2010 Mar 20; 262(2). PMID: 20236628    Free PMC article.
Review.
Identification of human CD4+ T cell populations with distinct antitumor activity.
Michelle H Nelson, Hannah M Knochelmann, +12 authors, Chrystal M Paulos.
Sci Adv, 2020 Sep 17; 6(27). PMID: 32937437    Free PMC article.
Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence.
Stefanie R Bailey, Michelle H Nelson, +9 authors, Chrystal M Paulos.
Nat Commun, 2017 Dec 08; 8(1). PMID: 29213079    Free PMC article.
Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer.
T Xiang, H Long, +6 authors, B Zhu.
Oncogene, 2013 Dec 24; 34(2). PMID: 24362529
Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.
Lucia De Monte, Michele Reni, +7 authors, Maria Pia Protti.
J Exp Med, 2011 Feb 23; 208(3). PMID: 21339327    Free PMC article.
Highly Cited.
EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.
Katherine L Morel, Anjali V Sheahan, +34 authors, Leigh Ellis.
Nat Cancer, 2021 Apr 27; 2(4). PMID: 33899001    Free PMC article.
Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response.
Mariëtte I E van Poelgeest, Marij J P Welters, +24 authors, Sjoerd H van der Burg.
Clin Cancer Res, 2016 Jan 28; 22(10). PMID: 26813357
Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
Philip W Kantoff, Celestia S Higano, +11 authors, IMPACT Study Investigators.
N Engl J Med, 2010 Sep 08; 363(5). PMID: 20818862
Highly Cited.
Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.
David Y Oh, Serena S Kwek, +17 authors, Lawrence Fong.
Cell, 2020 Jun 05; 181(7). PMID: 32497499    Free PMC article.
T cell metabolism drives immunity.
Michael D Buck, David O'Sullivan, Erika L Pearce.
J Exp Med, 2015 Aug 12; 212(9). PMID: 26261266    Free PMC article.
Highly Cited. Review.
Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
Margaretha G M Roemer, Robert A Redd, +26 authors, Margaret A Shipp.
J Clin Oncol, 2018 Feb 03; 36(10). PMID: 29394125    Free PMC article.
Highly Cited.
An essential role for the IL-2 receptor in Treg cell function.
Takatoshi Chinen, Arun K Kannan, +7 authors, Alexander Y Rudensky.
Nat Immunol, 2016 Oct 21; 17(11). PMID: 27595233    Free PMC article.
Highly Cited.
The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells.
Violaine François, Sabrina Ottaviani, +8 authors, Pierre van der Bruggen.
Cancer Res, 2009 May 14; 69(10). PMID: 19435913
Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18.
Biliang Hu, Jiangtao Ren, +5 authors, Carl H June.
Cell Rep, 2017 Sep 28; 20(13). PMID: 28954221    Free PMC article.
Highly Cited.
Leukocyte composition of human breast cancer.
Brian Ruffell, Alfred Au, +3 authors, Lisa M Coussens.
Proc Natl Acad Sci U S A, 2011 Aug 10; 109(8). PMID: 21825174    Free PMC article.
Highly Cited.
Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy.
Miren Zuazo, Hugo Arasanz, +12 authors, David Escors.
EMBO Mol Med, 2019 Jul 06; 11(7). PMID: 31273938    Free PMC article.
Highly Cited.
Cancer immunotherapy using checkpoint blockade.
Antoni Ribas, Jedd D Wolchok.
Science, 2018 Mar 24; 359(6382). PMID: 29567705    Free PMC article.
Highly Cited. Review.
Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
Mark E Dudley, James C Yang, +17 authors, Steven A Rosenberg.
J Clin Oncol, 2008 Sep 24; 26(32). PMID: 18809613    Free PMC article.
Highly Cited.
Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy.
Sangeeta Goswami, Irina Apostolou, +10 authors, Padmanee Sharma.
J Clin Invest, 2018 Jun 16; 128(9). PMID: 29905573    Free PMC article.
Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: potential synergistic effect with chemotherapy response.
Yann Godet, Elizabeth Fabre, +14 authors, Olivier Adotévi.
Clin Cancer Res, 2012 Mar 13; 18(10). PMID: 22407833
Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies.
Spencer C Wei, Nana-Ama A S Anang, +8 authors, James P Allison.
Proc Natl Acad Sci U S A, 2019 Oct 23; 116(45). PMID: 31636208    Free PMC article.
Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype.
Daniel Hirschhorn-Cymerman, Sadna Budhu, +10 authors, Jedd D Wolchok.
J Exp Med, 2012 Sep 26; 209(11). PMID: 23008334    Free PMC article.
Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia.
Jae H Park, Isabelle Rivière, +12 authors, Michel Sadelain.
N Engl J Med, 2018 Feb 01; 378(5). PMID: 29385376    Free PMC article.
Highly Cited.
Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism.
Fabrice Benchetrit, Arnaud Ciree, +7 authors, Eric Tartour.
Blood, 2002 Mar 06; 99(6). PMID: 11877287
Highly Cited.
The two faces of IL-6 in the tumor microenvironment.
Daniel T Fisher, Michelle M Appenheimer, Sharon S Evans.
Semin Immunol, 2014 Mar 08; 26(1). PMID: 24602448    Free PMC article.
Highly Cited. Review.
Tim-3 and its role in regulating anti-tumor immunity.
Madhumita Das, Chen Zhu, Vijay K Kuchroo.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258697    Free PMC article.
Highly Cited. Review.
Systemic Immunity Is Required for Effective Cancer Immunotherapy.
Matthew H Spitzer, Yaron Carmi, +10 authors, Edgar G Engleman.
Cell, 2017 Jan 24; 168(3). PMID: 28111070    Free PMC article.
Highly Cited.
Th9 cells promote antitumor immune responses in vivo.
Yong Lu, Sungyoul Hong, +10 authors, Qing Yi.
J Clin Invest, 2012 Oct 16; 122(11). PMID: 23064366    Free PMC article.
Highly Cited.
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Stephan A Grupp, Michael Kalos, +10 authors, Carl H June.
N Engl J Med, 2013 Mar 27; 368(16). PMID: 23527958    Free PMC article.
Highly Cited.
A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer.
Daniela Fenoglio, Paolo Traverso, +16 authors, Gilberto Filaci.
Cancer Immunol Immunother, 2013 Apr 18; 62(6). PMID: 23591981
Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumour, leading to generation of endogenous memory responses to non-targeted tumour epitopes.
Kunyu Li, Braeden Donaldson, +4 authors, Sarah Young.
Clin Transl Immunology, 2017 Nov 09; 6(10). PMID: 29114389    Free PMC article.
CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
P Shrikant, A Khoruts, M F Mescher.
Immunity, 1999 Nov 05; 11(4). PMID: 10549630
Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival.
Geoffrey J Markowitz, Lauren S Havel, +10 authors, Vivek Mittal.
JCI Insight, 2018 Jul 13; 3(13). PMID: 29997286    Free PMC article.
Combination Immunotherapy with CAR T Cells and Checkpoint Blockade for the Treatment of Solid Tumors.
Rachel Grosser, Leonid Cherkassky, Navin Chintala, Prasad S Adusumilli.
Cancer Cell, 2019 Nov 13; 36(5). PMID: 31715131    Free PMC article.
Review.
Combination of High Dose Hypofractionated Radiotherapy with Anti-PD1 Single Dose Immunotherapy Leads to a Th1 Immune Activation Resulting in a Complete Clinical Response in a Melanoma Patient.
Clara Milhem, Olivier Moralès, +5 authors, Nadira Delhem.
Int J Mol Sci, 2020 Sep 19; 21(18). PMID: 32942768    Free PMC article.
Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors.
Katy Milne, Martin Köbel, +5 authors, Brad H Nelson.
PLoS One, 2009 Jul 31; 4(7). PMID: 19641607    Free PMC article.
Highly Cited.
Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion.
Zhi-Jian Ye, Qiong Zhou, +5 authors, Huan-Zhong Shi.
J Immunol, 2010 Oct 19; 185(10). PMID: 20952674
CD4+ T cell help in cancer immunology and immunotherapy.
Jannie Borst, Tomasz Ahrends, +2 authors, Wolfgang Kastenmüller.
Nat Rev Immunol, 2018 Jul 31; 18(10). PMID: 30057419
Highly Cited. Review.
Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor.
Magalie Dosset, Yann Godet, +13 authors, Olivier Adotévi.
Clin Cancer Res, 2012 Oct 04; 18(22). PMID: 23032748
Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma.
Peter J Wersäll, Henric Blomgren, +3 authors, Christer Svedman.
Acta Oncol, 2006 Jun 09; 45(4). PMID: 16760190
Th9 cells, new players in adaptive immunity.
Edgar Schmitt, Matthias Klein, Tobias Bopp.
Trends Immunol, 2013 Nov 13; 35(2). PMID: 24215739
Review.
Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection.
Maria Moeller, Nicole M Haynes, +8 authors, Phillip K Darcy.
Blood, 2005 Jul 21; 106(9). PMID: 16030195
Distinct prognostic value of circulating anti-telomerase CD4+ Th1 immunity and exhausted PD-1+/TIM-3+ T cells in lung cancer.
Caroline Laheurte, Magalie Dosset, +14 authors, Olivier Adotévi.
Br J Cancer, 2019 Jul 31; 121(5). PMID: 31358938    Free PMC article.
Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity.
Mojgan Ahmadzadeh, Anna Pasetto, +4 authors, Steven A Rosenberg.
Sci Immunol, 2019 Jan 13; 4(31). PMID: 30635355    Free PMC article.
Highly Cited.
Tumor stroma and chemokines control T-cell migration into melanoma following Temozolomide treatment.
Kar Wai Tan, Maximilien Evrard, +7 authors, Jean-Pierre Abastado.
Oncoimmunology, 2015 May 08; 4(2). PMID: 25949877    Free PMC article.
CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy.
Hiroshi Kagamu, Shigehisa Kitano, +12 authors, Kunihiko Kobayashi.
Cancer Immunol Res, 2019 Dec 25; 8(3). PMID: 31871122
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
Christina Curtis, Sohrab P Shah, +29 authors, Samuel Aparicio.
Nature, 2012 Apr 24; 486(7403). PMID: 22522925    Free PMC article.
Highly Cited.
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1.
Naomi N Hunder, Herschel Wallen, +7 authors, Cassian Yee.
N Engl J Med, 2008 Jun 21; 358(25). PMID: 18565862    Free PMC article.
Highly Cited.
A signature of immune function genes associated with recurrence-free survival in breast cancer patients.
Maria Libera Ascierto, Maciej Kmieciak, +10 authors, Masoud H Manjili.
Breast Cancer Res Treat, 2011 Apr 12; 131(3). PMID: 21479927    Free PMC article.
Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer.
Dengbo Ji, Can Song, +6 authors, Jin Gu.
J Immunother Cancer, 2020 Oct 28; 8(2). PMID: 33106387    Free PMC article.
Prognostic value of CD4+ T lymphopenia in non-small cell lung Cancer.
Guillaume Eberst, Dewi Vernerey, +11 authors, Virginie Westeel.
BMC Cancer, 2022 May 14; 22(1). PMID: 35546670    Free PMC article.