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Article ; Online: The local microenvironment matters in preclinical basic and translational studies of cancer immunology and immunotherapy.

Ho, William W / Pittet, Mikael J / Fukumura, Dai / Jain, Rakesh K

2022 Volume 40, Issue 7, Page(s) 701–702

MeSH term(s)	Humans ; Immunologic Factors ; Immunotherapy ; Neoplasms/therapy ; Tumor Microenvironment
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2022-06-16
Publishing country	United States
Document type	Letter
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2022.05.016
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Article ; Online: Exercise intensity governs tumor control in mice with breast cancer.

Gomes-Santos, Igor L / Kumar, Ashwin S / Hausmann, Franziska / Meyer, Max N / Shiferaw, Sarah Z / Amoozgar, Zohreh / Jain, Rakesh K / Fukumura, Dai

Frontiers in immunology

2024 Volume 15, Page(s) 1339232

Abstract: Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity.: Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or ... ...

Abstract	Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity. Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity. Results: We found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream. Conclusion: These findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.
MeSH term(s)	Humans ; Mice ; Animals ; Exercise Therapy ; Running ; CD8-Positive T-Lymphocytes ; Physical Conditioning, Animal ; Neoplasms
Language	English
Publishing date	2024-03-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1339232
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Article ; Online: Implications of a granulocyte-high glioblastoma microenvironment in immune suppression and therapy resistance

Krishnan, Shanmugarajan / Amoozgar, Zohreh / Fukumura, Dai / Jain, Rakesh K

The Journal of pathology

2021 Volume 254, Issue 2, Page(s) 105–108

Abstract: The failure of anti-VEGF/R and immune checkpoint therapies to improve overall survival in Phase III clinical trials in glioblastoma (GBM) is considered to be due in part to the prevalent immunosuppression in the GBM tumor microenvironment. Immune ... ...

Abstract	The failure of anti-VEGF/R and immune checkpoint therapies to improve overall survival in Phase III clinical trials in glioblastoma (GBM) is considered to be due in part to the prevalent immunosuppression in the GBM tumor microenvironment. Immune suppression is mediated in part by resident microglia and bone-marrow-derived myeloid cells recruited during tumor progression. A paper by Blank et al published in a recent issue of The Journal of Pathology proposes a myeloid cell-mediated mechanism that could contribute to resistance to anti-VEGF/R in GBM patients. A granulocyte-rich GBM tumor microenvironment may push the associated microglia/macrophages to exhibit an activated and immune suppressive phenotype. The identification of pro-angiogenic factors produced by microglia/macrophages and granulocytes in such a tumor microenvironment may offer new targets for improving antiangiogenic therapy of GBM beyond VEGF. Further, consideration of parameters such as IDH status, corticosteroid dosage, tumor mutational burden, gender, vascular function, and pericyte coverage could exploit current immunotherapies to the fullest to reprogram the granulocyte-rich immunosuppressive GBM tumor microenvironment to an immunostimulatory one. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
MeSH term(s)	Brain Neoplasms ; Glioblastoma ; Granulocytes ; Humans ; Immunosuppression Therapy ; Tumor Microenvironment
Language	English
Publishing date	2021-03-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.5637
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Article ; Online: Combined transarterial and transvenous embolization of multi-hole pial arteriovenous fistula with large varix.

Yamada, Hiroki / Akiyama, Takenori / Kamamoto, Dai / Yoshida, Keisuke / Fukumura, Mariko / Toda, Masahiro

The neuroradiology journal

2022 Volume 35, Issue 5, Page(s) 640–646

Abstract: Background: Pial arteriovenous fistula (AVF) is a vascular fistulous disease in which the cerebral pial artery and vein are directly connected without the intervening nidus within a sub-pial space. Multi-hole pial AVFs, wherein multiple feeders flow ... ...

Abstract	Background: Pial arteriovenous fistula (AVF) is a vascular fistulous disease in which the cerebral pial artery and vein are directly connected without the intervening nidus within a sub-pial space. Multi-hole pial AVFs, wherein multiple feeders flow into one drainer, are usually formed with complex angioarchitecture and are difficult to treat. Methods: A rare case of an adult patient with hereditary hemorrhagic telangiectasia and multi-hole pial AVF was described. A 23-year-old woman was referred to our hospital. She was previously diagnosed with left cerebellar pial AVF with multiple feeders (bilateral superior cerebellar artery and common trunk of the left anterior inferior cerebellar artery and posterior inferior cerebellar) and large varix that had been untreated for 9 years. The enlargement of the large varix with the new second varix formation was revealed by angiography. Although asymptomatic, considered to be a risk for future hemorrhage was the continuous high hemodynamic stress. Results: Endovascular embolization was performed by securing safe transarterial Conclusions: Performing combined transarterial and transvenous embolization in a well-balanced manner was considered to treat multi-hole pial AVF to provide a safe and effective embolization.
MeSH term(s)	Adult ; Arteriovenous Fistula/complications ; Arteriovenous Fistula/diagnostic imaging ; Arteriovenous Fistula/therapy ; Cerebral Arteries ; Embolization, Therapeutic/methods ; Enbucrilate ; Female ; Humans ; Varicose Veins/complications ; Varicose Veins/diagnostic imaging ; Varicose Veins/therapy ; Young Adult
Chemical Substances	Enbucrilate (F8CEP82QNP)
Language	English
Publishing date	2022-04-28
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2257770-1
ISSN	2385-1996 ; 1971-4009 ; 1120-9976
ISSN (online)	2385-1996
ISSN	1971-4009 ; 1120-9976
DOI	10.1177/19714009221096829
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Article ; Online: Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction.

Agrud, Anass / Subburaju, Sivan / Goel, Pranay / Ren, Jun / Kumar, Ashwin Srinivasan / Caldarone, Barbara J / Dai, Wangde / Chavez, Jesus / Fukumura, Dai / Jain, Rakesh K / Kloner, Robert A / Vasudevan, Anju

Scientific reports

2022 Volume 12, Issue 1, Page(s) 4922

Abstract: Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial ... ...

Abstract	Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABA
MeSH term(s)	Animals ; Endothelial Cells/metabolism ; Hypertension/genetics ; Hypertension/metabolism ; Mice ; Mice, Knockout ; Receptors, GABA-A/metabolism ; gamma-Aminobutyric Acid/metabolism
Chemical Substances	Gabrb3 protein, mouse ; Receptors, GABA-A ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2022-03-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-08806-9
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Article ; Online: Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice.

Dong, Xinyue / Ren, Jun / Amoozgar, Zohreh / Lee, Somin / Datta, Meenal / Roberge, Sylvie / Duquette, Mark / Fukumura, Dai / Jain, Rakesh K

Journal for immunotherapy of cancer

2022 Volume 11, Issue 3

Abstract: Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the ... ...

Abstract	Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells' delivery and antitumor activity. We previously showed that blocking vascular endothelial growth factor (VEGF) signaling can normalize tumor vessels in murine and human tumors, including GBM, breast, liver, and rectal carcinomas. Moreover, we demonstrated that vascular normalization can improve the delivery of CD8+ T cells and the efficacy of immunotherapy in breast cancer models in mice. In fact, the US FDA (Food and drug administration) has approved seven different combinations of anti-VEGF drugs and immune checkpoint blockers for liver, kidney, lung and endometrial cancers in the past 3 years. Here, we tested the hypothesis that anti-VEGF therapy can improve the delivery and efficacy of CAR-T cells in immunocompetent mice bearing orthotopic GBM tumors. We engineered two syngeneic mouse GBM cell lines (CT2A and GSC005) to express EGFRvIII-one of the most common neoantigens in human GBM-and CAR T cells to recognize EGFRvIII. We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.
MeSH term(s)	United States ; Animals ; Mice ; Humans ; Glioblastoma/pathology ; Vascular Endothelial Growth Factor A ; Immunotherapy, Adoptive ; ErbB Receptors ; Vascular Endothelial Growth Factors ; Tumor Microenvironment
Chemical Substances	Vascular Endothelial Growth Factor A ; ErbB Receptors (EC 2.7.10.1) ; Vascular Endothelial Growth Factors ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2022-10-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005583
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Article ; Online: Targeted embolisation for coexisting conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas with a varix on a shared drainer

Yoshida, Keisuke / Niimi, Yasunari / Kamamoto, Dai / Fukumura, Mariko / Imai, Ryotaro / Nagoshi, Narihito / Akiyama, Takenori

British journal of neurosurgery

2020 Volume 37, Issue 5, Page(s) 1200–1205

Abstract: Background: The coexistence of vascular malformations in the conus medullaris and cauda equina has been rarely reported, and the complex angioarchitecture in multiple arteriovenous lesions remains poorly understood.: Case description: A 17-year-old ... ...

Abstract	Background: The coexistence of vascular malformations in the conus medullaris and cauda equina has been rarely reported, and the complex angioarchitecture in multiple arteriovenous lesions remains poorly understood. Case description: A 17-year-old woman presented with a sudden-onset, stepwise worsening of weakness and pain in the bilateral legs. Angiography revealed conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas. One of the drainers was shared between the coexisting lesions and harboured a varix. Targeted embolisation of a fistulous point in the conus lesion was performed with precaution to prevent occluding the common drainage route, which led to symptom improvement with angiographical diminishment of the varix. Conclusions: Recognising that communications between drainers can be observed in multiple spinal arteriovenous lesions is important in facilitating a safe embolisation. Cautious assessment of angiogram with fusion images of cone-beam computed tomography and volumetric T2 magnetic resonance imaging can help in establishing the diagnosis and treatment strategy.
MeSH term(s)	Female ; Humans ; Adolescent ; Cauda Equina/diagnostic imaging ; Spinal Cord/diagnostic imaging ; Spinal Cord/pathology ; Arteriovenous Malformations/complications ; Arteriovenous Malformations/diagnostic imaging ; Arteriovenous Malformations/therapy ; Arteriovenous Fistula/complications ; Arteriovenous Fistula/diagnostic imaging ; Arteriovenous Fistula/therapy ; Magnetic Resonance Imaging ; Varicose Veins/complications ; Varicose Veins/diagnostic imaging ; Varicose Veins/therapy
Language	English
Publishing date	2020-10-09
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	639029-8
ISSN	1360-046X ; 0268-8697
ISSN (online)	1360-046X
ISSN	0268-8697
DOI	10.1080/02688697.2020.1830948
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Article: Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma.

Jain, Rakesh / Krishnan, Shanmugarajan / Lee, Somin / Amoozgar, Zohreh / Subudhi, Sonu / Kumar, Ashwin / Posada, Jessica / Lindeman, Neal / Lei, Pinji / Duquette, Mark / Roberge, Sylvie / Huang, Peigen / Andersson, Patrik / Datta, Meenal / Munn, Lance / Fukumura, Dai

Research square

2023

Abstract: Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. ... ...

Abstract	Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. Acquired resistance to αPD1 was found to be associated with the upregulation of Wnt7b and β-catenin protein levels in GBM in patients and in a clinically relevant, stem-rich GBM model. Combining the porcupine inhibitor WNT974 with αPD1 prolonged the survival of GBM-bearing mice. However, this combination had a dichotomous response, with a subset of tumors showing refractoriness. WNT974 and αPD1 expanded a subset of DC3-like dendritic cells (DCs) and decreased the granulocytic myeloid-derived suppressor cells (gMDSCs) in the tumor microenvironment (TME). By contrast, monocytic MDSCs (mMDSCs) increased, while T-cell infiltration remained unchanged, suggesting potential TME-mediated resistance. Our preclinical findings warrant the testing of Wnt7b/β-catenin combined with αPD1 in GBM patients with elevated Wnt7b/β-catenin signaling.
Language	English
Publishing date	2023-12-26
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3707472/v1
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Article ; Online: Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction

Anass Agrud / Sivan Subburaju / Pranay Goel / Jun Ren / Ashwin Srinivasan Kumar / Barbara J. Caldarone / Wangde Dai / Jesus Chavez / Dai Fukumura / Rakesh K. Jain / Robert A. Kloner / Anju Vasudevan

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 12

Abstract: Abstract Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early ... ...

Abstract	Abstract Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor β3 subunit endothelial cell conditional knockout (Gabrb3 ECKO ) mice, the β3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3 ECKO telencephalon that persists in the adult neocortex. Gabrb3 ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3 ECKO mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3 ECKO mice. The Gabrb3 ECKO mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated ‘worm-like’ nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3 ECKO mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Cancer immunology research

2024 Volume 12, Issue 4, Page(s) 400–412

Abstract: Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract ... ...

Abstract	Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.
MeSH term(s)	Animals ; Humans ; Mice ; CD8-Positive T-Lymphocytes ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/metabolism ; Cisplatin/therapeutic use ; CTLA-4 Antigen/antagonists & inhibitors ; Gemcitabine/therapeutic use ; Tumor Microenvironment
Chemical Substances	Cisplatin (Q20Q21Q62J) ; CTLA-4 Antigen ; Gemcitabine
Language	English
Publishing date	2024-01-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0486
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