Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain

Mughal, Sadaf S.; Teuber‐Hanselmann, Sarah; Pierscianek, Daniela; Sucker, Antje; Jansen, Philipp; Schimming, Tobias; Klode, Joachim; Reifenberger, Julia; Felsberg, Jörg; Keyvani, Kathy; Brors, Benedikt; Sure, Ulrich; Reifenberger, Guido; Schadendorf, Dirk; Helfrich, Iris

doi:10.3389/fimmu.2020.00120

Cited by 34 publications

(19 citation statements)

References 76 publications

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“…We do not attribute the differences between the two cohorts to the higher number of melanoma-infiltrated lymph nodes included in EcM compared to other cohorts, because these distinct immune cell subsets were not significantly different between EcM in lymph nodes versus EcM in non-lymph nodes. Furthermore, craniotomy specimens from the UPMC cohort had not previously received radiation, much like in previous studies (31,37,38). We confirmed that gdT cells are variably present in MBM.…”

Section: Discussionsupporting

confidence: 86%

“…The UNC-CH cohort is significantly smaller compared to the UPMC cohort, including the patient subset with high TILs and subsequent treatment with immune checkpoint inhibitors that trends to live the longest compared to all other groups. However, UNC-CH's sample size is comparable to other previously reported craniotomy datasets (31,37,38). Furthermore, OS was the only clinical endpoint that was used in this study.…”

Section: Discussionmentioning

confidence: 58%

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Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases

et al. 2021

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BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 58%

Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases

et al. 2021

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“…In vitro stimulation of monocytes with IFNγ increased the M2/M1 ratio, while silencing of IDO in monocytes resulted in upregulation of pro-inflammatory M1-macrophages (74). In melanoma, macrophages constituted the predominant source of IDO expression in brain metastases (145). In agreement with these observations, IDO expression was detected in CD163 + (M2-type) macrophages infiltrating the tumor microenvironment in Hodgkin lymphoma, and associated with shortened survival in these patients (71).…”

Section: Immune Cellsmentioning

confidence: 63%

IDO Expression in Cancer: Different Compartment, Different Functionality?

2020

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Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

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“…However, not all patients obtained substantial benefit from ICI treatment. Importantly, a recent study suggested that IDO enzyme might represent a suitable target in this particular clinical context to enhance the efficacy of ICIs in the brain, being a major product of macrophage/microglia populations infiltrating the TME of melanoma metastases in the central nervous system [ 138 ].…”

Section: Clinical Trials Combining Immune Checkpoint Inhibitors Anmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma

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et al. 2020

Cancers

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Immune checkpoint inhibitors (ICIs) represent a promising therapeutic intervention for a variety of advanced/metastatic solid tumors, including melanoma, but in a large number of cases, patients fail to establish a sustained anti-tumor immunity and to achieve a long-lasting clinical benefit. Cells of the tumor micro-environment such as tumor-associated M2 macrophages (M2-TAMs) have been reported to limit the efficacy of immunotherapy, promoting tumor immune evasion and progression. Thus, strategies targeting M2-TAMs have been suggested to synergize with immune checkpoint blockade. This review recapitulates the molecular mechanisms by which M2-TAMs promote cancer immune evasion, with focus on the potential cross-talk between pharmacological interventions targeting M2-TAMs and ICIs for melanoma treatment.

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Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain

Abstract: The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Cited by 34 publications

References 76 publications

Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases

Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases

IDO Expression in Cancer: Different Compartment, Different Functionality?

Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma

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