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

Hirschhorn-Cymerman, Daniel; Budhu, Sadna; Kitano, Shigehisa; Liu, Cailian; Zhao, Feng; Zhong, Hong; Lesokhin, Alexander M.; Avogadri-Connors, Francesca; Yuan, Jianda; Li, Yanyun; Houghton, Alan N.; Merghoub, Taha; Wolchok, Jedd D.

doi:10.1084/jem.20120532

Cited by 132 publications

(140 citation statements)

References 63 publications

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“…Our data suggest that this tumor recognition bias of Treg may be exploited by approaches that induce Treg conversion into MHC class II/peptide-reactive effector cells that directly kill tumor cells (21)(22)(23). These considerations suggest that protocols for transfer of TAA-specific CD4 T cells may benefit from approaches that down-regulate Helios expression by CD4 Tregs to obtain increased antitumor reactivity from both conventional CD4 cells and Helios-deficient converted Tregs.…”

Section: Discussionmentioning

confidence: 89%

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Nakagawa

Sido

Reyes

et al. 2016

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

133

131

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Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.inflammation | tumor microenvironment | effector cytokines |

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Section: Discussionmentioning

confidence: 89%

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Nakagawa

Sido

Reyes

et al. 2016

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

133

131

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“…Eomes was also shown to be expressed by a subset of memory T lymphocytes generated after adoptive transfer of Th2 cells into a nude host (10). More generally, a significant CD4 + Eomes + population has been described during systemic 4-1BB-mediated stimulation (11,57,58). In this work, we further extended the analysis of Eomes + CD4 + T cells and found that Eomes is expressed by a sizeable amount of CD4 + T cells in different in vivo settings, from systemic activation during colitis and EAE induction to the noninflammatory response to oral Ags.…”

Section: Discussionmentioning

confidence: 97%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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“…Two recent studies using B-cell lymphoma and melanoma models confirm our observation of intratumoral Treg depletion following OX86 administration, which may support a common mechanism of OX86 antitumor efficacy in other tumor models. 21,30 Other studies did not report major changes in intratumoral Tregs following administration of OX86 antibody, which may relate to the tumor model and/or the kinetics of their evaluation. 22,31 Therefore, additional tumor efficacy studies would be particularly informative in models that recapitulate the progression of human cancer, such as genetically engineered mouse models.…”

Section: Fcgrs Mediate Antitumor Activity Of Ox86 Y Bulliard Et Almentioning

confidence: 99%

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy

et al. 2014

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Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcc receptor (FccR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FccRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FccRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3 þ regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FccR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FccR-expressing immune cells, and facilitate subsequent antitumor immunity. Agonistic antibodies targeting co-stimulatory tumor necrosis factor superfamily receptors (TNFRs) expressed by T cells, such as GITR (CD357) or OX40 (CD134), have been shown to enhance the proliferation and activation of isolated T cells. [1][2][3][4] Moreover, in preclinical tumor efficacy studies, these agonistic antibodies have shown potent tumoricidal activity. [5][6][7] The current model stipulates that agonistic antibodies targeting GITR, OX40 and other costimulatory receptors on T cells directly enhance the cytotoxic effector function of T cells, while counteracting the immunosuppressive effects of immune-regulatory populations, such as regulatory T cells (Tregs). [8][9][10][11] We recently reported that an agonistic antibody targeting GITR (DTA-1) requires the engagement of activating FcgRs but not the inhibitory FcgR (FcgRIIB) to mediate antitumor activity in mice. 12 This finding challenges the notion that FcgRIIB-mediated crosslinking is generally required for the in vivo activities of agonistic antibodies targeting TNFRs. [13][14][15] Importantly, DTA-1 administration triggered the rapid and selective elimination of intratumoral T cells, particularly those of the Treg lineage, as defined by FoxP3 expression. The extent of Treg depletion in the tumor microenvironment directly correlated with the antitumor efficacy. A similar mechanism was observed for antibodies targeting the non-TNFR immunoregulatory molecule CTLA-4. 12,16 A common feature of GITR and CTLA-4 is their high expression by intratumoral populations of T cells, with Tregs expressing the highest levels of each receptor. 12,17,18 Here, we investigated whether antibody-mediated intratumoral T-cell depletion might con...

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

Abstract: OX40 engagement induces a cytotoxic CD4+ T cell subpopulation to eradicate advance melanomas

Cited by 132 publications

References 63 publications

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy

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