Elsevier

Seminars in Immunology

Volume 52, February 2021, 101477
Seminars in Immunology

Review
Harnessing TH9 cells in cancer immunotherapy

https://doi.org/10.1016/j.smim.2021.101477Get rights and content

Highlights

  • •

    TH9 mediate potent anticancer functions against melanoma upon adoptive transfer.

  • •

    IL-9 and IL-21 mediate TH9 cell anticancer functions.

  • •

    Co-signalling receptor targeting can harness TH9 cell anticancer functions.

  • •

    PD-1 signalling restrains TH9 cell effector functions.

  • •

    Circulating TH9 cell frequency may predict anti-PD-1 therapy efficacy in humans.

Abstract

CD4 T cell effector subsets not only profoundly affect cancer progression, but recent evidence also underscores their critical contribution to the anticancer efficacy of immune checkpoint inhibitors. In 2012, the two seminal studies suggested the superior antimelanoma activity of TH9 cells over other T cell subsets upon adoptive T cell transfer. While these findings provided great impetus to investigate further the unique functions of TH9 cells and explore their relevance in cancer immunotherapy, the following questions still remain outstanding: are TH9 cell anticancer functions restricted to melanoma? What are the factors favouring TH9 cell effector functions? What is the contribution of TH9 cells to cancer immunotherapy treatments? Can TH9 cells be identified in humans and, if so, what is their clinical relevance? By reviewing the studies addressing these questions, we will discuss how TH9 cells could be therapeutically harnessed for cancer immunotherapy strategies.

Section snippets

CD4 T cells shape cancer progression and response to immunotherapy

Immune cells can eliminate cancer cells. Investigations into the abilities of immune cells to prevent cancer development were pioneered by Sir Mac Farlane Burnet who proposed in 1957 the cancer immunosurveillance hypothesis, i.e. the ability of immune cells to eliminate cancer cells before they form a clinically detectable tumour [1]. Subsequent studies confirmed the relevance of immune cells in limiting cancer outgrowth not only in preclinical models but also in humans [2]. Such knowledge has

IL-9, a cytokine not originally coined with anticancer functions

IL-9 is the major effector cytokine secreted by TH9 cells. IL-9 was initially characterized in 1988 as a protein secreted from T cell clones and acting as a T cell growth factor [29]. Further research has demonstrated that naïve T cells could secrete IL-9 upon activation, and this was potentiated by TGF-β and IL-4(30). The functional properties of IL-9 were subsequentially documented for transformed T cells. IL-9 indeed supports the proliferation of transformed murine T cells and human T cell

Induction of TH9 cell anticancer responses in tumor-bearing hosts through vaccination

As initially reported by Purwar et al., the frequency of tumor-infiltrating TH9 cells is low [25], prompting for therapeutic strategies to enhance their induction in vivo. Administration of TGF-β, IL-4 or IL-33 in mice failed to enhance TH9 cell frequency [48]. However, other attempts to generate TH9 cells in vivo using immunization with tumor antigens and immunomodulation were successful. Staphylococcal enterotoxin B (SEB) is a superantigen that potently activates T cells [53]. Two studies

How to characterize human TH9 cells in cancer?

While mouse TH2, TH17 and Treg cells were proposed to secrete low levels of IL-9 upon activation [69], TH9 cells were characterised as high producers of IL-9 and low producers of TH1, TH2 and TH17 cytokines [23]. Purwar et al. first interrogated whether human TH9 cells could be identified in a cancer setting. Following their identification in the blood of human memory T cells secreting IL-9, but not IFNγ, IL-4 or IL-17, the authors found that these TH9 cells were also present in the skin of

Conclusions

Since the characterization of TH9 cells in 2008, substantial progress has been made into understanding the molecular mechanisms accounting for their superior anticancer functions. In preclinical models, this has resulted in the identification of therapeutic strategies that were able to harness TH9 cell anticancer functions in vivo. It is notable that the anticancer activity of TH9 cells was frequently established in adoptive transfer settings. In a setting mimicking the clinical situation, we

Author contributions

L.A. drafted the manuscript and the figures. I.B.L. edited manuscript and the figures. L.A. and I.B.L. approved the final paper. Figures were created with BioRender.com.

Funding

This work was funded by grants from the Conseil Régional de Bourgogne and FEDER, the Agence Nationale de la Recherche [ANR-11-LABX-0021], the Acteria Foundation, the European Research Council (ERC) (grant agreement N°677251) and the Fondation ARC [DOC20190509200].

Declaration of Competing Interest

L.A. has performed consultancy work for Roche, Merck, Bristol-Myers Squibb, and Orega Biotech. L.A. was a recipient of a research grant from Sanofi.

References (81)

  • S.A. Rosenberg et al.

    Adoptive cell transfer as personalized immunotherapy for human cancer

    Science

    (2015)
  • F. Pagès et al.

    Effector memory T cells, early metastasis, and survival in colorectal cancer

    N. Engl. J. Med.

    (2005)
  • J. Galon et al.

    Type, density, and location of immune cells within human colorectal tumors predict clinical outcome

    Science

    (2006)
  • M. Dosset et al.

    Modulation of determinant factors to improve therapeutic combinations with immune checkpoint inhibitors

    Cells

    (2020)
  • P.C. Tumeh et al.

    PD-1 blockade induces responses by inhibiting adaptive immune resistance

    Nature

    (2014)
  • S.T. Ferris et al.

    cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity

    Nature

    (2020)
  • R. Zander et al.

    CD4+ t cell help is required for the formation of a cytolytic CD8+ t cell subset that protects against chronic infection and Cancer

    Immunity

    (2019)
  • L. Apetoh et al.

    Consensus nomenclature for CD8 + T cell phenotypes in cancer

    Oncoimmunology

    (2015)
  • N.N. Hunder et al.

    Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1

    N. Engl. J. Med.

    (2008)
  • M. Zuazo et al.

    Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy

    EMBO Mol. Med.

    (2019)
  • H. Kagamu et al.

    CD4 + T-cell immunity in the peripheral blood correlates with response to Anti-PD-1 therapy

    Cancer Immunol. Res.

    (2020)
  • J.A. Bluestone et al.

    The functional plasticity of T cell subsets

    Nat. Rev. Immunol.

    (2009)
  • T.R. Mosmann et al.

    Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins

    J. Immunol.

    (1986)
  • W.H. Fridman et al.

    The immune contexture in cancer prognosis and treatment

    Nat. Rev. Clin. Oncol.

    (2017)
  • W.H. Fridman et al.

    The immune contexture in human tumours: impact on clinical outcome

    Nat. Rev. Cancer

    (2012)
  • L. Wang et al.

    IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway

    J. Exp. Med.

    (2009)
  • H. Berger et al.

    SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth

    Cancer Res.

    (2013)
  • V. Dardalhon et al.

    IL-4 inhibits TGF-beta-induced Foxp3+ t cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector t cells

    Nat. Immunol.

    (2008)
  • M. Veldhoen et al.

    Transforming growth factor-beta’ reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset

    Nat. Immunol.

    (2008)
  • R. Purwar et al.

    Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells

    Nat. Med.

    (2012)
  • Y. Lu et al.

    Th9 cells promote antitumor immune responses in vivo

    J. Clin. Invest.

    (2012)
  • R.R. Almeida et al.

    Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumour immunity

    Br. J. Cancer

    (2020)
  • L. Apetoh

    Anticancer effects of the microbiota: how the microbiome shapes the development of IL-9-producing T cells

    Br. J. Cancer

    (2020)
  • C. Uyttenhove et al.

    Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity

    Proc. Natl. Acad. Sci. U. S. A.

    (1988)
  • E. Schmitt et al.

    IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma

    J. Immunol.

    (1994)
  • M. Fischer et al.

    Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin’s lymphoma

    Leukemia

    (2003)
  • J.C. Renauld et al.

    Thymic lymphomas in interleukin 9 transgenic mice

    Oncogene

    (1994)
  • Y. Fu et al.

    STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

    Nat. Commun.

    (2020)
  • F.A. Houssiau et al.

    IL-2 dependence of IL-9 expression in human T lymphocytes

    J. Immunol.

    (1992)
  • H. Nakatsukasa et al.

    The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) t cells

    Nat. Immunol.

    (2015)
    • View full text
    © 2021 Elsevier Ltd. All rights reserved.