CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells

Robertson, Shelly J.; Messer, Ronald J.; Carmody, Aaron B.; Mittler, Robert S.; Burlak, Christopher; Hasenkrug, Kim J.

doi:10.4049/jimmunol.180.8.5267

Cited by 45 publications

(50 citation statements)

References 58 publications

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“…In addition, the significance of regulatory T cells (Tregs) after anti-CD137 therapy has not been well defined and remains contradictory. Because CD137 is not only expressed on activated effector T cells, but also on CD4 + Foxp3 + Tregs (7), it is unknown whether activation of Tregs through CD137 may drive increased suppressive Treg activity as previously suggested (8).…”

mentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

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confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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“…CD137 is expressed on a wide variety of cells and anti-CD137 antibodies may have activities other than as simple agonists. 5 The role of CD137 in T reg -cell function is uncertain 6 and it paradoxically ameliorates certain autoimmune diseases. 7,8 More broadly, the immune systems of mice are significantly different from those of humans and several other approaches that have yielded promising data in mice have proved ineffective in humans.…”

Section: Org Frommentioning

confidence: 99%

“…Where this has been done, it was concluded that it is primarily CMV that is responsible for driving these "ageassociated" changes. 6 Therefore, it may be proposed that the increased levels of expression of negative receptors by CD8 cells is in response to the necessity of maintaining these cells in an activated state as effectors responsible for CMV immunosurveillance. An antiproliferative, apoptosis-resistant, CD28 Ϫ , KIR ϩ phenotype (commonly but perhaps erroneously assumed to reflect "senescence") might, in fact, be protective and help to retain essential effector cells because CMV-specific cells constantly exposed to viral antigens might otherwise be stimulated to proliferate until they reached exhaustion and were clonally deleted.…”

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confidence: 99%

The doctor's dilemma: stimulating T cells

Vickers

2009

Blood

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“…10 The effect of CD137 ligation on T regs is not as clearly understood, with conflicting reports showing both stimulation and inhibition of the immunosuppressive functions of these cells. [10][11][12][13][14] Consistent with the costimulatory function of CD137 on T convs , agonistic mAbs against this receptor have been shown to provoke powerful tumor-specific T-cell responses capable of eradicating tumor cells in a variety of murine tumor models including sarcoma, mastocytoma, glioma, colon carcinoma, and myeloma. 3,15 Anti-CD137 mAb has now entered clinical trials for solid tumors (melanoma, renal cell carcinoma, lung cancer, and ovarian cancer) but little is known about its potential therapeutic effect in lymphoma.…”

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confidence: 99%

Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion

Houot¹,

Goldstein²,

Kohrt³

et al. 2009

Blood

122

117

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Despite the success of passive immunotherapy with monoclonal antibodies (mAbs), many lymphoma patients eventually relapse. Induction of an adaptive immune response may elicit active and longlasting antitumor immunity, thereby preventing or delaying recurrence. Immunomodulating mAbs directed against immune cell targets can be used to enhance the immune response to achieve efficient antitumor immunity. Anti-CD137 agonistic mAb has demonstrated antitumor efficacy in various tumor models and has now entered clinical trials for the treatment of solid tumors. Here, we investigate the therapeutic potential of anti-CD137 mAb in lymphoma. We found that human primary lymphoma tumors are infiltrated with CD137 ؉ T cells. We therefore hypothesized that lymphoma would be susceptible to treatment with anti-CD137 agonistic mAb. Using a mouse model, we demonstrate that anti-CD137 therapy has potent antilymphoma activity in vivo. The antitumor effect of anti-CD137 therapy was mediated by both natural killer (NK) and CD8 T cells and induced long-lasting immunity. Moreover, the antitumor activity of anti-CD137 mAb could be further enhanced by depletion of regulatory T cell (T regs ). These results support the evaluation of anti-CD137 therapy in clinical trials for patients with lymphoma. (Blood. 2009;114:3431-3438) IntroductionLymphoma is responsive to immunotherapy. 1 Despite the success of passive immunotherapy with monoclonal antibodies (mAbs) directed against tumor cells (eg, anti-CD20, rituximab), many lymphoma patients eventually relapse. Active immunotherapy for the treatment of lymphoma aims to induce an adaptive and long-lasting antitumor immune response to prevent or prolong time to recurrence. Although antitumor immune cells can be found in cancer patients, these cells may be rendered ineffective in eradicating cancer due to tumor-induced immunosuppression. 2 Monoclonal antibodies that target and modulate the function of tumor-reactive immune cells may enhance antitumor immune responses to therapeutic levels. 3 Targeting the immune environment of the tumor as opposed to the malignant cells presents unique advantages. Whereas targeting tumor cells with mAbs requires a tumor-specific antigen (Ag), stimulating or inhibiting nonmalignant immune cells is expected to be applicable across different patients and cancer types. Further, unlike tumor cells that may mutate into therapy-resistant clones under selective pressure of mAb treatment, normal immune cells are not expected to be clonally selected for such mutations. Finally, whereas tumor-directed mAbs are considered passive immunotherapy and therefore offer only transient efficacy, targeting the immune system with mAbs aims to induce and/or potentiate an active and long-lasting immune response against cancer.Antibody-mediated T-cell modulation can be accomplished in several ways, including (1) enhancing costimulation on conventional T cells (T convs ; eg, agonistic anti-CD137 and anti-OX40 mAbs); (2) blocking negative signals on T convs (eg, antagonistic anti-CTLA4 mAb); o...

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CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells

Cited by 45 publications

References 58 publications

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

The doctor's dilemma: stimulating T cells

Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion

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