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 Montreal, 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://kaminska-lab.nencki.edu.pl
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland