Anantha Marisetty

The University of Texas MD Anderson Cancer Center

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Amy B. Heimberger

Northwestern University

Dexing Fang

The University of Texas MD Anderson Cancer Center

Martina Ott

The University of Texas MD Anderson Cancer Center

Gregory N. Fuller

The University of Texas MD Anderson Cancer Center

Cynthia Kassab

The University of Texas MD Anderson Cancer Center

Aria Sabbagh

The University of Texas MD Anderson Cancer Center

James P. Long

The University of Texas MD Anderson Cancer Center

Ling‐Yuan Kong

The University of Texas MD Anderson Cancer Center

Yuuri Hashimoto

Okayama University

Jared K. Burks

The University of Texas MD Anderson Cancer Center

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The University of Texas MD Anderson Cancer Center

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The University of Texas Health Science Center at Houston

Baylor College of Medicine

John Wiley & Sons (United States)

Neurological Surgery

Hudson Institute

Northwestern University

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Northwestern Medicine

Northwestern University

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Figure S5 from Verteporfin Inhibits PD-L1 through Autophagy and the STAT1–IRF1–TRIM28 Signaling Axis, Exerting Antitumor Efficacy

Jiyong Liang Lulu Wang Chao Wang Jianfeng Shen Bojin Su

Supplemental Figure S5

Verteporfin

HMGA2

10.1158/2326-6066.22543366.v1

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LMD-20. Immune Suppressive Macrophages and Signal Transducer and Activator of Transcription 3 (STAT3) Expression are common in Melanoma Leptomeningeal Disease

Neuro-Oncology Advances (2021)

Hinda Najem Anantha Marisetty Craig Horbinski Jared K. Burks Amy B. Heimberger

Abstract Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological impairments and has a dismal outcome with a median survival of 1.8 months. Despite the therapeutic benefit of targeted therapies and immunotherapies for most kinds of Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3 T cells, CD68+ monocytes, CD163 immune suppressive macrophages, CD11c+ antigen presenting cells (APCs) in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD163+ macrophage is the most frequent immune cell population in the LMD TME. Occasional CD3+ T cells and CD11c+ APC are also identified, although the latter has concurrent expression of CD163. STAT3 nuclear localization is heterogeneously expressed in the various immune cell populations. Occasional immune cluster interactions can be seen in the tumor stroma and the tumor edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells, but is enriched for immune suppression and innate immunity.

CD163

10.1093/noajnl/vdab071.045

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DDEL-06. HEAT-ACTIVATED DOXORUBICIN UPTAKE FACILITATED BY LASER INTERSTITIAL THERMAL THERAPY

Neuro-Oncology (2022)

Prazwal Athukuri Karina Moreno Yuhui Yang Malcolm F. McDonald Sung-Ho Lee

Abstract Although surgery has been shown to provide a survival benefit in patients with glioblastoma multiforme (GBM), tumor location and geometry may restrict maximal resection. Additionally, the margin of resection cavity contains infiltrating tumor cells that result in recurrence and therapy resistance. Laser interstitial thermal therapy (LITT) is a treatment modality that uses thermal energy to destroy tumor cells. LITT is useful for tumors that are not appropriate for conventional surgical resection. Our laboratory has developed a LITT model to study LITT in a genetically engineered mouse model of GBM. The combination of heat activated nanoparticles and LITT represents an opportunity to target the infiltrating tumor margin, extending the treatment penumbra. We hypothesized that heat-activated liposomes containing doxorubicin (ThermoDox, Celsion) would demonstrate infiltration into the brain parenchyma after treatment with LITT. We treated tumor-bearing mice with LITT or sham (laser fiber implanted but not activated) after either ThermoDox (5mg/kg) or PBS infusion, 30 minutes before performing LITT or sham treatment. We euthanized these mice 1 hour after LITT or sham treatment, harvested brains, and performed immunofluorescence to identify doxorubicin in parenchymal cells. Doxorubicin was identified in 100% of mice treated with LITT following ThermoDox administration which is in contrast with groups treated with LITT and PBS, sham and ThermoDox, and sham and PBS. Here, we show that heat-activated nanoparticles are disrupted through hyperthermia followed by the release of doxorubicin only in the presence of hyperthermia, which paves way for the clinical use of ThermoDox as adjunct chemotherapy following LITT in treatment-resistant GBM treatment.

Infiltration (HVAC)

Parenchyma

Hyperthermia therapy

10.1093/neuonc/noac209.352

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REST–miR-21–SOX2 axis maintains pluripotency in E14Tg2a.4 embryonic stem cells

Stem Cell Research (2015)

Sanjay K. Singh Anantha Marisetty Pratheesh Sathyan Mohamedi N. Kagalwala Zhaoyang Zhao

Our previous studies have shown that the regulatory network that maintains pluripotency in mouse embryonic stem cells (mESCs) is regulated in a context-dependent manner and can be modulated, at least in part, by re-calibration of an intracellular network of pluripotency factors as well as cues arising from the extracellular matrix. The transcriptional repressor REST represses miR-21 and, thus, regulates self-renewal in E14Tg2a.4 mESCs cultured in the absence of mouse embryonic fibroblast feeder cell effects. However, how miR-21 connects to the nuclear regulatory network has not been clear. Here, we show that miR-21, a direct target of REST-mediated repression, directly targets Sox2. Exogenously added miR-21 to mESCs decreases the expression of Sox2, decreasing mESC self-renewal, and this effect of miR-21 on mESC self-renewal can be blocked by expression of exogenous Sox2. Conversely, destabilization of Sox2 by miR-21 can be blocked by anti-miR-21. Thus, the REST-miR-21-Sox2 axis connects REST to the core nuclear pluripotency regulators in E14Tg2a.4 mESCs cultured in the absence of feeder cells.

Homeobox protein NANOG

Rex1

10.1016/j.scr.2015.05.003

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Figure S2 from Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy

Martina Ott Cynthia Kassab Anantha Marisetty Yuuri Hashimoto Jun Wei

Figure S2 shows survival curves from the radiation dose-finding study in the GL261 model.

10.1158/1078-0432.22475639.v1

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Data from Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy

Martina Ott Cynthia Kassab Anantha Marisetty Yuuri Hashimoto Jun Wei

<div>AbstractPurpose:Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma.Experimental Design:C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood–brain barrier–penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.Results:The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control P < 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions.Conclusions:This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.</div>

10.1158/1078-0432.c.6529118

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Figure S3 from Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy

Martina Ott Cynthia Kassab Anantha Marisetty Yuuri Hashimoto Jun Wei

Figure S3 shows survival curves for two independent mouse experiments.

10.1158/1078-0432.22475636

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Figure S2 from Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy

Martina Ott Cynthia Kassab Anantha Marisetty Yuuri Hashimoto Jun Wei

Figure S2 shows survival curves from the radiation dose-finding study in the GL261 model.

10.1158/1078-0432.22475639

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Verteporfin Inhibits PD-L1 through Autophagy and the STAT1–IRF1–TRIM28 Signaling Axis, Exerting Antitumor Efficacy

Cancer Immunology Research (2020)

Jiyong Liang Lulu Wang Chao Wang Jianfeng Shen Bojin Su

Abstract Programmed cell death 1 ligand 1 (PD-L1) is a key driver of tumor-mediated immune suppression, and targeting it with antibodies can induce therapeutic responses. Given the costs and associated toxicity of PD-L1 blockade, alternative therapeutic strategies are needed. Using reverse-phase protein arrays to assess drugs in use or likely to enter trials, we performed a candidate drug screen for inhibitors of PD-L1 expression and identified verteporfin as a possible small-molecule inhibitor. Verteporfin suppressed basal and IFN-induced PD-L1 expression in vitro and in vivo through Golgi-related autophagy and disruption of the STAT1–IRF1–TRIM28 signaling cascade, but did not affect the proinflammatory CIITA-MHC II cascade. Within the tumor microenvironment, verteporfin inhibited PD-L1 expression, which associated with enhanced T-lymphocyte infiltration. Inhibition of chromatin-associated enzyme PARP1 induced PD-L1 expression in high endothelial venules (HEV) in tumors and, when combined with verteporfin, enhanced therapeutic efficacy. Thus, verteporfin effectively targets PD-L1 through transcriptional and posttranslational mechanisms, representing an alternative therapeutic strategy for targeting PD-L1.

Verteporfin

10.1158/2326-6066.cir-19-0159

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Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target

Journal of Clinical Investigation (2018)

Jun Wei Anantha Marisetty Brett Schrand Konrad Gabrusiewicz Yuuri Hashimoto

Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin αvβ5 (ITGαvβ5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.

Osteopontin

10.1172/jci121266

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Citations (288)