The role of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in down-regulating human alloresponses has recently been controversially debated. We here demonstrate that human monocyte-derived dendritic cells (mDCs) can be endowed with sustained IDO competence in vitro by 48-hour activation with lipopolysaccharide (LPS) and interferon-gamma (IFN-␥). IFN-␥ also amplified proinflammatory cytokine secretion during activation. Yet, on reculture after activation cytokine production ceased, whereas IDO enzymatic activity IntroductionIndoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan catabolism, has attracted attention for its proposed role in tolerance induction. 1,2 IDO, when expressed in antigen presenting cells (APCs), such as dendritic cells (DCs), establishes a microenvironment that at the DC/T-cell interface is depleted of tryptophan and enriched with tryptophan metabolites. Because of this alteration of the intercellular microenvironment, IDO activity has been suggested to impair T-cell responses. 3,4 The mechanisms of IDO-mediated inhibition include that T cells stimulated under tryptophan-depleted conditions are impaired to undergo full cell cycle progression 3,5 and are susceptible to apoptotic cell death. 6,7 Furthermore, it has been reported that IDO-expressing DCs can expand naturally occurring regulatory T cells. 8 In a murine model Fallarino et al 9 have shown that IDO activity supported the generation of adaptive regulatory T cells. Likewise, human IDOexpressing tumor cells have been reported to induce CD4 ϩ CD25 ϩ regulatory T cells. 10 Most recently, the previously recognized immunoregulatory activity of human plasmacytoid DCs has been related to IDO activity. 11 Thus, IDO-mediated down-regulation of T-cell responses has been suggested to be involved in a multitude of immunoregulatory processes, for example, pregnancy, 12 tumor growth, 13 and the induction of tolerance in transplantation (reviewed in Hainz et al 14 ).IDO expression is not a constitutive feature of human DCs in homeostatic immunologic conditions but requires induction. Among the multiple mediators of IDO induction (reviewed in Puccetti 15 ), interferon-␥ (IFN-␥) plays a prominent role. 16 IFN-␥ has generally been considered a prototypic proinflammatory cytokine (reviewed in Schoenborn and Wilson 17 ); compelling evidence, however, supports the ability of IFN-␥ to promote anti-inflammatory responses. [18][19][20] The ability of IFN-␥ to induce IDO has been suggested as a critical factor linked to this anti-inflammatory activity. 21,22 In our previous studies addressing possible mechanisms of the immunodeficient state after hematopoietic stem cell transplantation, 23 we found that monocytes after hematopoietic stem cell transplantation were particularly sensitive to respond to an exposure to IFN-␥ with an accelerated release of tryptophan metabolite kynurenine, and, thus, to turn into suppressor cells. This finding suggested the possibility that an augmented IDO activity in recipients of a hemat...
• Marrow CD81 T-cell infiltrates may be a novel predictor of response to donor lymphocyte infusions in patients with relapsed CML.• Reversal of T-cell exhaustion is tightly linked to effective antileukemia responses to donor lymphocyte infusions.Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4 1 DLI in the pre-tyrosine kinase inhibitor era. Immunohistochemical analysis of pretreatment marrow revealed that the presence of >4% marrow-infiltrating CD8 1 (but not CD4 1 ) T cells predicted DLI response, even in the setting of high leukemia burden. Furthermore, mRNA expression profiling of marrow-infiltrating T cells of a subset of responders compared with nonresponders revealed enrichment of T-cell exhaustionspecific genes in pretreatment T cells of DLI responders and significant downregulation of gene components in the same pathway in responders in conjunction with clinical response. Our data demonstrate that response to DLI is associated with quantity of preexisting marrow CD8 1 T cells and local reversal of T-cell exhaustion. Our studies implicate T-cell exhaustion as a therapeutic target of DLI and support the potential use of novel anti-PD1/PDL1 agents in lieu of
Background. Patients with advanced hematologic malignancies remain at risk for relapse following reducedintensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. Methods. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.Results. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8 + T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8 + T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Conclusion.Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance longterm leukemia control following allo-HSCT.Trial registration. Clinicaltrials.gov NCT00442130.
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