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Ontak reduces the immunosuppressive tumor environment and enhances successful therapeutic vaccination in HER-2/neu-tolerant mice

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Abstract

Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT + (neuT +) triple transgenic mice represent an improvement over neuT + mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85–94) (p85) CTL and HER-2(776–790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 × neuT + Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy.

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Abbreviations

Tregs:

Regulatory T cells

Tg:

Transgenic

Teffs:

Effector T cell

FasL:

Fas ligand

PENT:

Pentamer

Tm:

Tetramer

TIL:

Tumor infiltrating lymphocytes

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cancer Immunology and Immunotherapy Center, St Savas Cancer Hospital, 171 Alexandras Avenue, 115 22, Athens, Greece

    Angelos D. Gritzapis, Ioannis F. Voutsas & Constantin N. Baxevanis

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  1. Angelos D. Gritzapis
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  2. Ioannis F. Voutsas
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  3. Constantin N. Baxevanis
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Correspondence to Constantin N. Baxevanis.

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Gritzapis, A.D., Voutsas, I.F. & Baxevanis, C.N. Ontak reduces the immunosuppressive tumor environment and enhances successful therapeutic vaccination in HER-2/neu-tolerant mice. Cancer Immunol Immunother 61, 397–407 (2012). https://doi.org/10.1007/s00262-011-1113-4

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