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A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.

ABSTRACT: Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigate Pt(IV)-(D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer "immuno-chemotherapy". Compound 2 effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, inhibiting IDO by transcriptional deregulation of the autocrine-signaling loop IDO-AHR-IL6, which blocks kynurenine production and promotes T-cell proliferation. Additionally, 1 and 2 display low toxicity in mice and are stable in blood. To our knowledge, this construct is the first Pt drug candidate with immune checkpoint blockade properties.

SUBMITTER: Awuah SG

PROVIDER: S-EPMC4772771 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.

Awuah Samuel G SG Zheng Yao-Rong YR Bruno Peter M PM Hemann Michael T MT Lippard Stephen J SJ

Journal of the American Chemical Society 20151118 47

Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigate Pt(IV)-(D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer "immuno-chemothe ...[more]

PMID: 26561720

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Project description:Successful long-term treatment of type-1 diabetes mainly relies on replacement of β-cells via islet transplantation. Donor shortage is one of the main obstacles preventing transplantation from becoming the treatment of choice. Although animal organs could be an alternative source for transplantation, common immunosuppressive treatments demonstrate low efficacy in preventing xenorejection. Immunoprotective effects of indoleamine 2,3-dioxygenase (IDO) on T-cell mediated allorejection has been extensively studied. Our studies revealed that IDO expression by fibroblasts, induced apoptosis in T-cells while not affecting non-immune cell survival/function. Since macrophages play a pivotal role in xenograft rejection, herein we investigated the effect of IDO-induced tryptophan deficiency/kynurenine accumulation on macrophage function/survival. Moreover, we evaluated the local immunosuppressive effect of IDO on islet-xenograft protection. Our results indicated that IDO expression by bystander fibroblasts significantly reduced the viability of primary macrophages via apoptosis induction. Treatment of peritoneal macrophages by IDO-expressing fibroblast conditioned medium significantly reduced their proinflammatory activity through inhibition of iNOS expression. To determine whether IDO-induced tryptophan starvation or kynurenine accumulation is responsible for macrophage apoptosis and inhibition of their proinflammatory activity, Raw264.7 cell viability and proinflammatory responses were evaluated in tryptophan deficient medium or in the presence of kynurenine. Tryptophan deficiency, but not kynurenine accumulation, reduced Raw264.7 cell viability and suppressed their proinflammatory activity. Next a three-dimensional islet-xenograft was engineered by embedding rat islets within either control or IDO-expressing fibroblast-populated collagen matrix. Islets morphology and immune cell infiltration were then studied in the xenografts transplanted into the C57BL/6 mouse renal sub-capsular space. Local IDO significantly decreased the number of infiltrating macrophages (11 ± 1.47 vs. 70.5 ± 7.57 cells/HPF), T-cells (8.75 ± 1.03 vs. 75.75 ± 5.72 cells/HPF) and iNOS expression in IDO-expressing xenografts versus controls. Islet morphology remained intact in IDO-expressing grafts and islets were strongly stained for insulin/glucagon compared to control. These findings support the immunosuppressive role of IDO on macrophage-mediated xeno-rejection.

Project description:High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.

Dataset Information

A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.

Publications

A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.

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