Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL− Tumors

Abstract

I matinib mesylate (Gleevec) therapy remains the standard of care for patients with chronic myelogenous leukemia (CML).3 Designed as a selective competitive inhibitor of the Abelson (ABL) tyrosine kinases (BCR-ABL, v-ABL, c-ABL), this drug leads to growth arrest or apoptosis (1, 2). Imatinib also displays strong activity against the platelet-derived growth factor receptor, c-kit receptor, ABL-related gene, and their fusion proteins (1-3) and thus has also been used for the therapy of gastrointestinal stromal tumors with mutations in c-kit (2).However, the specificity of this molecule may be broader than originally expected, and it is becoming increasingly evident that imatinib also inhibits key tyrosine kinases in immune cells. The exact nature of imatinib effects (activation or suppression) on lymphocytes or dendritic cells remains controversial. Inhibition of CD4 ϩ or CD8 ϩ T cell proliferation and activation by imatinib has been documented (4 -8). Some reports have further highlighted the negative effect of imatinib on the TCR-induced ZAP70 signaling pathway identifying the leukocyte-specific protein tyrosine kinase (Lck) as a potential molecular target (4, 9). Similarly, a negative modulation of dendritic cell (DC) development by imatinib and a down-regulation of their Ag-presenting function have also been described (10 -12). In contrast to these findings, it has been reported that imatinib does not impede the immunogenicity of DC (13) and may enhance their Ag-presenting function (14). Additionally, some reports indicate that imatinib may foster DC-NK reciprocal activation, thereby promoting the antitumoral function of NK cells (15). CD4 ϩ CD25 ϩ regulatory T lymphocytes (Treg) critically contribute to the maintenance of self-tolerance and to the prevention of autoimmunity in animals and humans (16, 17). These suppressive cells have also been highlighted as major contributors in the establishment and persistence of cancer-induced immune tolerance (18,19). Treg expansion detected in the blood, lymph nodes, and spleens of tumor-bearing hosts (20 -23) may result from the conversion of CD4 ϩ CD25 Ϫ T cells into CD4 ϩ CD25 ϩ Treg (24) or from the proliferation of naturally occurring Treg (25). Tumorinduced Treg compromise the function of anti-tumor effector CD8 ϩ T cells, curtail CD4 ϩ T cell help, impede Ag-presenting cell activity (18,23,26) and therefore represent a major obstacle for successful cancer immunotherapy. In support of this concept, studies in humans and in animal models have demonstrated that attempts to disrupt Treg suppressive activity promote antitumoral immunity (20,27,28). Different strategies have thus been evaluated to deplete or inactivate Treg and include the use of anti-CD25 Abs, the IL-2/diphtheria toxin fusion protein, the immunotoxin The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.1 This work was supported in p...

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

“…Therefore, the overall antitumor effects exerted by TKIs may arise concurrently, or even primarily, from the bystander targeting of immune cells (Figure 3). The relevance of tumor-cell-extrinsic targets for imatinib is supported by the observations that GISTs not mutated in Kit or Pdgfra can exhibit (Yang et al, 2008), MDSCs (Ko et al, 2009) and DCs (Borg et al, 2004), molecules in the T-cell receptor (TCR) proximal signaling mediate TKI response in Treg (Larmonier et al, 2008). TKI resistance, confined to the tumor microenvironment, can be induced in MDSCs by the GM-CSF-R pathway (Ko et al, 2010).…”

“…Blockade of T-cell activation becomes beneficial in cancer immunotherapy when the targeted cells are immunomodulatory cells that favor tumor progression, such as Treg. Imatinib has been reported to decrease Treg-suppressive function in vitro and in vivo, an effect mostly due to the inhibited phosphorylation of ZAP70 and LAT molecules following T-cell receptor stimulation Larmonier et al, 2008).…”

Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host

“…A number of reports have documented seemingly contradictory immunomodulatory effects of tyrosine kinase inhibitors, ranging from impaired T-cell responses [23][24][25] to enhanced responses to vaccination. 26 Although this study was not designed to look at differences in vaccine-induced immune responses between imatinib-and dasatinib-treated patients, our results suggest that patients with CML treated with tyrosine kinase inhibitors can mount effective immune responses to H1N1 vaccination. Seasonal influenza vaccine fails to produce cross-reactive antibodies to pandemic H1N1 27 because H1N1 virus and conventional influenza strains differ in their hemagglutinin and neuraminidase sequences, the two surface proteins that are the primary targets of neutralizing antibodies.…”

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

“…However, in vitro studies showed that imatinib [31] and dasatinib impaired the proliferation and function of CD4 + CD25 + regulatory cells in a dose--dependent manner [32]. Further studies into the function of Tregs in patients treated with TKI are needed, especially given that encouraging data in a mouse model showed that imatinib enhanced active immunotherapy against BCR-ABL + tumors [33,34]. Finally, we analyzed the percentages of Th17 cells in peripheral blood of CML patients.…”