Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors

Platten, Michael; Doeberitz, Nikolaus von Knebel; Oezen, Iris; Wick, Wolfgang; Ochs, Katharina

doi:10.3389/fimmu.2014.00673

Cited by 270 publications

(294 citation statements)

References 55 publications

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“…Evidence suggests that the immune response may be impaired by upregulation of multiple checkpoint inhibitors and that these inhibitory pathways are upregulated in microsatellite unstable colorectal carcinomas. 18,[27][28][29] Most of these studies, however, classify microsatellite unstable colorectal carcinomas as a single group and do not consider the histologic heterogeneity of microsatellite unstable colorectal carcinomas. As such, we hypothesized Figure 1 Percentage of cases by histologic subtype demonstrating epithelial and stromal staining for IDO-1, tRNA(trp) or WARS, GBP5, and PD-L1.…”

Section: Discussionmentioning

confidence: 99%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

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Section: Discussionmentioning

confidence: 99%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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“…It provides an ideal immune-sanctuary site for tumor growth by its ability to locally mediate T-cell inactivation, tolerance and apoptosis [39]. For instance, the liver is rich in tryptophan 2,3-dioxygenase that degrades tryptophan along the kynurenine pathway, which might explain a local T-cell suppressive immune microenvironment [40]. Indeed, clinical studies in cutaneous melanoma have shown relatively poor responses to anti-PD-1 therapy in the setting of liver metastasis, with the liver metastasis also demonstrating lower rates of PD-L1 expression [41,42].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

et al. 2017

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Aim:To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Materials & methods: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. Results: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p < 0.0001). PD-1 expression on tumor-infiltrating lymphocytes was greater in MCM (73.6%; 67/91) than in MUM (51.1%; 23/45), respectively (p = 0.009). Conclusion: Significant differences exist in PD-L1 expression between MCM and MUM. The lower PD-L1 expression in MUM may provide a rationale for failure of PD-1 inhibitor therapy and suggests that immune evasion in this disease may occur via alternative mechanisms. Uveal melanoma originates from melanocytes in the choroid, ciliary body and iris of the eye [1]. It is the most common primary intraocular malignancy in adults and occurs almost exclusively in Caucasians, with an incidence of approximately 5-7/million/year in certain European populations [2]. In the USA, it represents about 5% of all melanoma diagnoses [1,3]. Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4]. Compared with cutaneous melanoma, uveal melanoma is characterized by its distinct genetic profile and clinical presentation, where most metastases are detected in the liver [5][6][7][8][9][10]. Once uveal melanoma metastasizes, prognosis is poor because metastatic uveal melanoma (MUM) tends to be widespread within the liver and only surgically resectable in some cases [11,12]. Therefore, there is an unmet need for investigating effective systemic therapies.Systemic immunotherapy with checkpoint inhibitors has vastly improved the treatment of metastatic cutaneous melanoma (MCM), leading to long-term durable responses [13,14]. MUM patients are often treated with immune checkpoint inhibitors identical to those used in the treatment of MCM (anti-programmed death-1 [PD-1] and anti-CTLA4 [Cytotoxic T-lymphocyte-associated protein 4] antibodies), either as monotherapy or in combination. Contrary to MCM, MUM demonstrates a poor response to these immune checkpoint blockades [15] (Table 1) [16][17][18][19][20][21][22][23] One of the mechanisms by which tumors evade the immune system is through upregulation and expression of PD-L1 protein on their surface. PD-L1 on tumor cells interacts with PD-1 receptor expressed on activated T cells, leading to T-cell exhaustion, anergy and ultimately, immune response abandonment [24,25]. Inhibition of the PD-1/PD-L1 interaction is the mechanism by which anti-PD-1 antibodies induce T-cell activation and antitumor effect.We evaluated the express...

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“…Local depletion of TRP suppresses T cell proliferation and induces cell death [43] . AHR activation reportedly induces differentiation of Treg cells [44] . …”

Section: T Cellsmentioning

confidence: 99%

Immunological aspect of the liver and metastatic uveal melanoma

Terai¹,

Mastrangleo²,

Sato³

2017

JCMT

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Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma. Key words:Uveal melanoma, metastasis, liver, liver microenvironment, immunotherapy ABSTRACTArticle history:

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Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors

Cited by 270 publications

References 55 publications

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

Immunological aspect of the liver and metastatic uveal melanoma

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