Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Abstract

IntroductionAcute myeloid leukemia (AML) with unfavorable cytogenetics has a poor outcome, even when treated with aggressive chemotherapy. 1,2 With chemoradiotherapy and hematopoietic stem cell transplantation, a graft-versus-leukemia effect can be observed even in patients with unfavorable cytogenetics. 3 Although donor lymphocyte infusion (DLI) given as adoptive immunotherapy after hematopoietic stem cell transplantation has improved the outcomes of certain types of leukemia, 4-6 for patients with AML, DLI has been less effective likely due at least in part to its rapid tumor progression. 7,8 As a result of the anti-AML effects of DLI and with the observation that antitumor-specific cytotoxic T cells (CTLs) can be generated in vitro from cancer patients, adoptive CTL therapy has been proposed for decades as cancer treatment. [9][10][11][12][13][14] However, the adoptive transfer of anti-AML-reactive CTLs alone has not solved the problem of AML disease recurrence. 15 In patients with chronic myelogenous leukemia, a complete remission was achieved in a patient with accelerated-phase disease after adoptive treatment with leukemia-reactive CTLs. 16 In rodents with minimal disease, CTL adoptive transfer also has not been uniformly curative despite the early transfer of large numbers of anti-AML-reactive CTLs. 17,18 Enhancing CTL function in vivo via the administration of supportive cytokine therapy such as interleukin-2 (IL-2), 20 and interferons 21 can improve antitumor efficacy but has been associated with substantial side effects. Therefore, recent studies have focused on eliminating the suppressive factors in the tumor environment to circumvent CTLs from inhibition. 22,23 T-regulatory cells (Tregs) are important regulators of immune responses in transplantation, 24,25 allergy, 26,27 and autoimmune disease. 28,29 In AML patients, the frequency of Tregs was noted to be significantly higher compared with healthy persons, likely due to increased proliferation. 30 Human AML cells have been noted to favor the conversion of CD4 ϩ 25 Ϫ T cells into Tregs via modulation of tryptophan catabolism. 31 Tregs that have been recruited to, or converted either before migration into or within the tumor environment, can have a profound inhibition on T cell-mediated immune response. 32 Multiple mechanisms have been defined to be responsible for the suppression, including secretion of transforming growth factor-␤ 33,34 and IL-10, 33,34 as well as inhibition of dendritic cell (DC) maturation. 33,35 Despite the great potential for Treg depletion in cancer therapies, the efficacy has been limited to prophylactic settings where depletion of Tregs is given before the establishment of tumor. 36,37 The present studies were undertaken to determine whether endogenous Tregs present at the site of AML dissemination constrained the antileukemia efficacy of anti-AML CTL adoptive transfer in a rodent model as a prelude to future clinical trials. We observed that AML progression correlated with increased Tregs at the sites of AML disease. Incr...

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

“…8 Hallet et al analyzed the efficacy of NK cells in a murine adoptive transfer model in which Tregs were depleted with an anti-CD25 antibody.…”

“…20,21 However, we acknowledge that the absence of donor NK cells in patients is likely the consequence of a variety of rejection mechanisms. 8,[22][23][24][25] Direct NK-cell inhibition via Treg membrane-bound transforming growth factor-b has been reported and may also contribute suppression of in vivo NK-cell expansion. 26 Targeting some proposed inhibitory mechanisms such as blockade of cytotoxic T-lymphocyte antigen 4, the programmed cell death protein 1 pathway, or inhibitors of indoleamine 2,3-dioxygenase may further unleash suppressed NK-mediated immunity.…”

“…7 In murine AML models, depletion of Tregs by anti-IL-2 receptor a monoclonal antibody or IL-2 diphtheria toxin fusion protein dramatically improved the efficacy of adoptive NK or cytotoxic T-cell immunotherapy. 8,9 IL2DT is a particularly attractive agent to test for the selective depletion of Tregs due to the short half-life, rapid internalization time, and induction of apoptosis, thus allowing for dosing regimens that will not affect adoptive immune therapy (ie, NK cells) infused just hours after IL2DT. 10 Thus, we tested host Treg depletion with IL2DT in our platform of lymphodepleting chemotherapy to enhance in vivo NK cell expansion and induction of remissions in refractory AML after adoptive NK cell transfer.…”

Umbilical cord blood graft engineering: challenges and opportunities

“…69 Data from mouse models is somewhat contradictory; tumor regression after IL-2-diphtheria toxin-mediated Treg depletion was seen in one model suggesting that Tregs may adversely affect disease-control. 70 In contrast, simultaneous adoptive transfer of Tregs and unselected donor T-cells in mismatched mouse transplant models showed protection from GvHD without impairing tumor control. 71,72 It has been suggested that this apparent specificity of Tregs for alloreactive T-cells rather than tumor-reactive T-cells may relate to a different mechanism for the development of GvHD and GVL effect.…”

Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice

“…Because IDO can be induced by IFN-g, IDO-negative cancer cells may be initiated to express IDO when exposed to an inflammatory context in the tumor microenvironment, and thereby hinder CD8 þ T-cell-mediated tumor regression before it can be effective (4,5,12). Recently, strong evidence has indicated that modification of the tumor microenvironment, such as the blockade of the TGF-b signaling pathway (15,16), inhibition of IDO (17,18), or depletion of Tregs (19,20) is able to augment the cytotoxicity of CD8 þ T cells.…”