Boże­na Kamińska

Tam­ing tumor microen­vi­ron­ment with siR­NAs and inno­v­a­tive nanocar­ri­ers in malig­nant gliomas

Abstract

Although immunother­a­py has achieved good results in var­i­ous can­cer types, a large pro­por­tion of patients does not ben­e­fit. In case of ther­a­py with check­point inhibitors, only 20 – 30% of the patients respond well. There is a grow­ing under­stand­ing that accu­mu­la­tion and repro­gram­ming of myeloid cells cre­ates a “cold” immuno­sup­pres­sive tumor microen­vi­ron­ment (TME) which results a poor infil­tra­tion and exhaus­tion of effec­tor T cells. Glioblas­toma (GBM) is a dead­ly brain tumor. Its tumor microen­vi­ron­ment is infil­trat­ed with myeloid cells which sup­port tumor pro­lif­er­a­tion, dif­fu­sive growth and impair respons­es to treat­ments. Using sin­gle cell and spa­tial tran­scrip­tomics, we unrav­eled iden­ti­ties of immune cells instru­men­tal for cre­at­ing cold TME, cell-cell com­mu­ni­ca­tion net­works and poten­tial targets. 

Arginase 1 (Arg1) abun­dant­ly expressed in glioma-asso­ci­at­ed microglia/​macrophages (GAMs) leads to deple­tion of L‑arginine required for pro­lif­er­a­tion of T cells and NK cells, con­tribut­ing to immuno­sup­pres­sion. We demon­strat­ed that arginase inhibitors reduce depen­dent inva­sion of human U87 MG and mouse GL261 glioma cells induced by the co-cul­ture with microglial cells. The can­di­date inhibitor while non effec­tive alone, improved anti­tu­mor effi­ca­cy of the PD1 block­ade. We devel­oped new siR­NA based strate­gies to reac­ti­vate anti­tu­mor immune respons­es in GBM by tar­get­ing Arg1 expres­sion in myeloid cells. We used opti­mized siR­NA Arg1 deliv­ery and gene knock­down in GAMs using man­nose-dec­o­rat­ed amphiphilic den­drimers (Man­AD). We designed and test­ed the man­nose-dec­o­rat­ed amphiphilic den­drimers (Man­AD) as car­ri­ers for ther­a­peu­tic siR­NA silenc­ing Arg1. Man­nose residues con­ferred tar­get­ing of the man­nose recep­tor (CD206) upreg­u­lat­ed on acti­vat­ed tumor asso­ci­at­ed myeloid cells. The biodis­tri­b­u­tion analy­sis showed hom­ing of Man­AD to the brain and GAMs. 

Admin­is­tra­tion of Arg1-tar­get­ing siR­NA com­plexed with Man­AD result­ed in decrease of Arg1 lev­els in myeloid cells (most­ly infil­trat­ing mono­cytes), which result­ed in the reduced tumor growth in mice. The anti­tu­mor effi­ca­cy of siR­NA Arg1 in man­nose-dec­o­rat­ed den­drimers was test­ed in com­bi­na­tion with anti-PD1. Alto­geth­er, our results demon­strate that phar­ma­co­log­ic or genet­ic inhi­bi­tion of arginase in glioma-asso­ci­at­ed myeloid cells could be a promis­ing strat­e­gy to awake anti­tu­mor immu­ni­ty and improve ther­a­py response in gliomas.

The study was sup­port­ed by Nation­al Cen­tre for Research and Devel­op­ment in Poland and French Nation­al Research Agency under the frame of the Era-Net EURO­NANOMED “INanoGun” project.

Bozena Kamin­s­ka¹_,Alek­san­dra Ellert-Mik­laszews­ka¹, Pauli­na Pilanc¹, Katarzy­na Poleszak¹, Dinesh Dhu­mal², Tom Rus­sel², Mar­i­on Casano­va², Sal­wador Cyra­nows­ki¹, Bea­ta Kaza¹, Ling Peng²

¹Nenc­ki Insti­tute of Exper­i­men­tal Biol­o­gy, War­saw, Poland

²Aix-Mar­seille Uni­ver­site, Cen­ter Inter­dis­ci­plinaire de Nanoscience de Mar­seille, Mar­seille, France

Biography/​Link

Bozena Kamin­s­ka grad­u­at­ed from the Fac­ul­ty of Biol­o­gy at the Uni­ver­si­ty of War­saw in 1985, and obtained her PhD in bio­chem­istry at the Nenc­ki Insti­tute of Exper­i­men­tal Biol­o­gy of the Pol­ish Acad­e­my of Sci­ences in 1991. In 1997 she has obtained habil­i­ta­tion at this insti­tu­tion, and in 2003 become a full pro­fes­sor. Cur­rent­ly she is work­ing at the Nenc­ki Insti­tute of Exper­i­men­tal Biol­o­gy PAS in War­saw, where she heads the Lab­o­ra­to­ry of Mol­e­c­u­lar Neu­ro­bi­ol­o­gy. Since 2009 she is the direc­tor of the Post­grad­u­ate School of Mol­e­c­u­lar Med­i­cine of the Med­ical Uni­ver­si­ty of War­saw. In 2016 she was elect­ed a cor­re­spond­ing mem­ber of the Pol­ish Acad­e­my of Sciences.

Her inter­na­tion­al train­ing encom­pass­es a post­doc­tor­al intern­ship at the McGill Uni­ver­si­ty in Mon­tréal, a vis­it­ing researcher at the Brain Research Insti­tute at UCLA in Los Ange­les and the vis­it­ing Nan­shan Schol­ar pro­fes­sor­ship at the Med­ical Uni­ver­si­ty of Guangzhou.

She spe­cial­izes in mol­e­c­u­lar neu­ro­bi­ol­o­gy, neu­ro-oncol­o­gy and tumor immunol­o­gy. Through mech­a­nis­tic under­stand­ing of the crosstalk between the immune sys­tem and tumor she aims to con­tribute to the design of nov­el immunomod­u­la­to­ry strate­gies to fight uncur­able brain tumors. She has pio­neered sin­gle-cell omics stud­ies of brain tumor microen­vi­ron­ment. In her career, she was a prin­ci­pal inves­ti­ga­tor in 44 domes­tic and inter­na­tion­al research grants, includ­ing grants from the Nation­al Sci­ence Cen­ter (Mae­stro, Har­mo­nia, Sym­pho­ny, OPUS), Nation­al Cen­ter for Research and Devel­op­ment (Strategmed 1, 2, 3), Foun­da­tion for Pol­ish Sci­ence (Mas­ter, Team-Tech Core Facil­i­ty), a NATO grant, EU sub­si­dies in two Frame­work Pro­grams and ERANET grants. She pro­mot­ed 27 doc­tors, 3 habil­i­tat­ed doc­tors and 10 Mas­ter students.

Her achieve­ments include 147 sci­en­tif­ic pub­li­ca­tions (e.g. in Nature Com­mu­ni­ca­tions, Cell and PNAS) cit­ed over 7,000 times (Hirsch index = 44) and 10 chap­ters in books.. Bozena Kamin­s­ka received a pres­ti­gious FNP Award in 2021.

https://​kamin​s​ka​-lab​.nenc​ki​.edu​.pl

Lab­o­ra­to­ry of Mol­e­c­u­lar Neu­ro­bi­ol­o­gy, Nenc­ki Insti­tute of Exper­i­men­tal Biol­o­gy of the Pol­ish Acad­e­my of Sci­ences, War­saw, Poland