Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models

被引：31

作者：

Datta, Meenal ^{[1
,14
]}

Chatterjee, Sampurna ^{[1
,15
]}

Perez, Elizabeth M. ^{[1
,2
,3
,4
,5
]}

Gritsch, Simon ^{[1
,2
,3
,4
]}

Roberge, Sylvie ^{[1
]}

Duquette, Mark ^{[1
]}

Chen, Ivy X. ^{[1
]}

Naxerova, Kamila ^{[1
,16
,17
]}

Kumar, Ashwin S. ^{[1
,6
]}

Ghosh, Mitraji ^{[1
,18
]}

Emblem, Kyrre E. ^{[1
,7
]}

Ng, Mei R. ^{[1
,15
]}

Ho, Willia W. ^{[1
,8
,19
]}

Kumar, Pragya ^{[1
]}

Krsihnan, Shanmugaraja ^{[1
,20
]}

Dong, Xinyu ^{[1
,15
]}

Speranza, Maria C. ^{[9
,10
]}

Neagu, Martha R. ^{[11
]}

Iorgulescu, Bryan ^{[9
]}

Huang, Raymond Y. ^{[12
]}

Youssef, Gilbert ^{[13
]}

Reardon, David A. ^{[9
,10
]}

Sharpe, Arlene H. ^{[4
,11
]}

Freeman, Gordon J. ^{[9
]}

Suva, Mario L. ^{[2
,3
,4
]}

Xu, Lei ^{[1
]}

Jain, Rakesh K. ^{[1
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA

[2] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[3] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[4] Broad Inst & Harvard, Cambridge, MA 02142 USA

[5] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[6] Harvard Massachusetts Inst, MIT, Technol Div Hlth Sci & Technol, Cambridge, MA 02142 USA

[7] Oslo Univ Hosp, Dept Phys & Computat Radiol, Div Radiol & Nucl Med, N-0372 Oslo, Norway

[8] MIT, Dept Chem Engn, Cambridge, MA 02142 USA

[9] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[11] Harvard Med Sch, Blavatnik Inst, Dept Immunol, Boston, MA 60064 USA

[12] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA

[13] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02215 USA

[14] Univ Notre Dame, Dept Aerosp & Mech Engn, Notre Dame, IN 46556 USA

[15] Takeda Pharmaceut Co Ltd, Cambridge, MA 02142 USA

[16] Massachusetts Gen Hosp, Ctr Syst Biol, Dept Radiol, Boston, MA 02114 USA

[17] Harvard Med Sch, Boston, MA 02114 USA

[18] Nencki Inst Expt Biol, Lab Mol Neurobiol, PL-02093 Warsaw, Poland

[19] ASTAR, Singapore Immunol Network, Singapore 138632, Singapore

[20] Agenus Inc, Lexington, MA 02421 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 06期

基金：

欧盟地平线“2020”;

关键词：

immune checkpoint blockers; glioblastoma; immune-related adverse events; tumor; microenvironment; biomarkers; ANGIOTENSIN-SYSTEM INHIBITORS; II RECEPTOR BLOCKERS; VASOGENIC EDEMA; CELL; MACROPHAGES; MICROGLIA; ACTIVATION; BENEFIT; TUMORS; IMPACT;

D O I：

10.1073/pnas.2219199120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glio-blastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

引用

页数：11

共 58 条

[1]

Ammons DT, 2022, CANCER RES COMMUN, V2, P1657, DOI [10.1158/2767-9764.CRC-22-0388, 10.1158/2767-9764.crc-22-0388]

[2] Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas [J].

Amoozgar, Zohreh ;

Kloepper, Jonas ;

Ren, Jun ;

Tay, Rong En ;

Kazer, Samuel W. ;

Kiner, Evgeny ;

Krishnan, Shanmugarajan ;

Posada, Jessica M. ;

Ghosh, Mitrajit ;

Mamessier, Emilie ;

Wong, Christina ;

Ferraro, Gino B. ;

Batista, Ana ;

Wang, Nancy ;

Badeaux, Mark ;

Roberge, Sylvie ;

Xu, Lei ;

Huang, Peigen ;

Shalek, Alex K. ;

Fukumura, Dai ;

Kim, Hye-Jung ;

Jain, Rakesh K. .

NATURE COMMUNICATIONS, 2021, 12 (01)

[3] Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma [J].

Arrieta, O ;

Guevara, P ;

Escobar, E ;

García-Navarrete, R ;

Pineda, B ;

Sotelo, J .

BRITISH JOURNAL OF CANCER, 2005, 92 (07) :1247-1252

[4] Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas [J].

Aslan, Katrin ;

Turco, Verena ;

Blobner, Jens ;

Sonner, Jana K. ;

Liuzzi, Anna Rita ;

Nunez, Nicolas Gonzalo ;

De Feo, Donatella ;

Kickingereder, Philipp ;

Fischer, Manuel ;

Green, Ed ;

Sadik, Ahmed ;

Friedrich, Mirco ;

Sanghvi, Khwab ;

Kilian, Michael ;

Cichon, Frederik ;

Wolf, Lara ;

Jaehne, Kristine ;

von Landenberg, Anna ;

Bunse, Lukas ;

Sahm, Felix ;

Schrimpf, Daniel ;

Meyer, Jochen ;

Alexander, Allen ;

Brugnara, Gianluca ;

Roeth, Ralph ;

Pfleiderer, Kira ;

Niesler, Beate ;

von Deimling, Andreas ;

Opitz, Christiane ;

Breckwoldt, Michael O. ;

Heiland, Sabine ;

Bendszus, Martin ;

Wick, Wolfgang ;

Becher, Burkhard ;

Platten, Michael .

NATURE COMMUNICATIONS, 2020, 11 (01)

[5] Conserved pan-cancer microenvironment subtypes predict response to immunotherapy [J].

Bagaev, Alexander ;

Kotlov, Nikita ;

Nomie, Krystle ;

Svekolkin, Viktor ;

Gafurov, Azamat ;

Isaeva, Olga ;

Osokin, Nikita ;

Kozlov, Ivan ;

Frenkel, Felix ;

Gancharova, Olga ;

Almog, Nava ;

Tsiper, Maria ;

Ataullakhanov, Ravshan ;

Fowler, Nathan .

CANCER CELL, 2021, 39 (06) :845-+

[6] Steroid-sparing effects of angiotensin-II inhibitors in glioblastoma patients [J].

Carpentier, A. F. ;

Ferrari, D. ;

Bailon, O. ;

Ursu, R. ;

Banissi, C. ;

Dubessy, A-L ;

Belin, C. ;

Levy, C. .

EUROPEAN JOURNAL OF NEUROLOGY, 2012, 19 (10) :1337-1342

[7] Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy [J].

Chauhan, Vikash P. ;

Chen, Ivy X. ;

Tong, Rong ;

Ng, Mei Rosa ;

Martin, John D. ;

Naxerova, Kamila ;

Wu, Michelle W. ;

Huang, Peigen ;

Boucher, Yves ;

Kohane, Daniel S. ;

Langer, Robert ;

Jain, Rakesh K. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (22) :10674-10680

[8] Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels [J].

Chauhan, Vikash P. ;

Martin, John D. ;

Liu, Hao ;

Lacorre, Delphine A. ;

Jain, Saloni R. ;

Kozin, Sergey V. ;

Stylianopoulos, Triantafyllos ;

Mousa, Ahmed S. ;

Han, Xiaoxing ;

Adstamongkonkul, Pichet ;

Popovic, Zoran ;

Huang, Peigen ;

Bawendi, Moungi G. ;

Boucher, Yves ;

Jain, Rakesh K. .

NATURE COMMUNICATIONS, 2013, 4

[9] A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade [J].

Chen, Ivy X. ;

Newcomer, Kathleen ;

Pauken, Kristen E. ;

Juneja, Vikram R. ;

Naxerova, Kamila ;

Wu, Michelle W. ;

Pinter, Matthias ;

Sen, Debattama R. ;

Singer, Meromit ;

Sharpe, Arlene H. ;

Jain, Rakesh K. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2020, 117 (38) :23684-23694

[10] HYALURONAN AND HYALURONECTIN IN THE EXTRACELLULAR-MATRIX OF HUMAN BRAIN-TUMOR STROMA [J].

DELPECH, B ;

MAINGONNAT, C ;

GIRARD, N ;

CHAUZY, C ;

MAUNOURY, R ;

OLIVIER, A ;

TAYOT, J ;

CREISSARD, P .

EUROPEAN JOURNAL OF CANCER, 1993, 29A (07) :1012-1017

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