Interferon-α-induced IL-6 improves immune and clinical benefits of regulatory T cell depletion as ovarian cancer immunotherapy — ASN Events
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  3. Interferon-α-induced IL-6 improves immune and clinical benefits of regulatory T cell depletion as ovarian cancer immunotherapy

Interferon-α-induced IL-6 improves immune and clinical benefits of regulatory T cell depletion as ovarian cancer immunotherapy (#238)

Suzanne R. Thibodeaux 1 , Srilaksmi Pandeswara 2 , Shawna Wall 2 , Vincent Hurez 2 , Lishi Sun 2 , Benjamin J. Daniel 2 , Ai-Jie Liu 2 , Leslie Wood 2 , Weiping Zou 3 , Tyler J. Curiel 2
  1. University of Pennsylvania, Philadelphia, PA, USA
  2. UT Health Science Center, San Antonio, TEXAS, United States
  3. University of Michigan, Ann Arbor, MI, USA

Tregs blunt anti-tumor immunity. Their depletion is effective treatment in mouse cancer models. Treg depletion in human trials is only partially effective, however. In our phase II ovarian cancer trial, denileukin diftitox (DT) depleted Tregs significantly in blood and the tumor microenvironment but without significant clinical efficacy. Interferon-α alone does not treat ovarian cancer effectively, but we now show that it significantly boosts immune and clinical effects of DT-mediated Treg depletion in human ovarian cancer. In the ID8 mouse ovarian cancer model, DT improved anti-tumor immunity and survival modestly. Interferon-α alone did not affect Treg function or numbers, but improved CD8+ T cell anti-tumor immunity. Adding interferon-α to DT significantly increased mouse survival versus either agent alone. Using type I IFNR-/- mice that are unable to mediate interferon-α signals, we showed that interferon-α boosted CD8+ T cell function independent of CD4+ T cell help through direct action on CD8+ T cells. In combination with DT, interferon-α reduced Treg function (without further reducing their numbers) through indirect effects on dendritic cells in vivo. In vitro we determined that interferon-α reduced Treg suppression and increased IL-6 in Treg suppression assays only when conventional dendritic cells were present. Anti-IL-6 antibody reversed the effect, and recombinant IL-6 recapitulated the effect in the absence of dendritic cells. When three ovarian cancer patients failed DT alone in the phase II trial, two experienced immunologic and clinical benefit by adding weekly pegylated interferon-α2a at 180 μg subcutaneously, with manageable toxicities. There was a trend for pegylated interferon-α2a to reduce Treg function and increase serum IL-6 when combined with DT, versus effects of DT alone in these 3 patients. IL-6 is generally detrimental to anti-tumor immunity and promotes carcinogenesis, but in specific instances it could be beneficial. These studies demonstrate novel immune and clinical interferon-α anti-cancer benefits that augment Treg depletion using approved agents for rapid clinical translation.