Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer

J. Sprooten, A. Vankerckhoven, I. Vanmeerbeek, DM. Borras, Y. Berckmans, R. Wouters, RS. Laureano, T. Baert, L. Boon, C. Landolfo, AC. Testa, D. Fischerova, C. Van Holsbeke, T. Bourne, V. Chiappa, W. Froyman, D. Schols, P. Agostinis, D....

. 2021 ; 9 (11) : . [pub] -

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22011996

BACKGROUND: Tumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers' detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification. METHODS: We used a data-driven in silico framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and whole-blood immune cell counts. Here, sFIS assay's ability to determine survival benefit or malignancy risk was validated in a discovery (n=32) and/or validation (n=699) patient cohorts. Lastly, we used an orthotopic murine metastatic OV model, with anti-OV therapy selection via in silico drug-target screening and murine serum screening via sFIS assay, to assess suitable in vivo immunotherapy options. RESULTS: In silico data-driven framework predicted that peripheral immunodynamics of patients with cancer might be best captured via analyzing myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) signaling and interferon-stimulated genes' (ISG) responses. This helped in conceptualization of an 'in sitro' (in vitro+in situ) sFIS assay, where human myeloid cells were exposed to patients' serum in vitro, to assess serum-induced (si)-NFκB or interferon (IFN)/ISG responses (as active signaling reporter activity) within them, thereby 'mimicking' patients' in situ immunodynamic status. Multiparametric serum profiling of patients with OV established that sFIS assay can: decode peripheral immunology (by indicating higher enrichment of si-NFκB over si-IFN/ISG responses), estimate survival trends (si-NFκB or si-IFN/ISG responses associating with negative or positive prognosis, respectively), and coestimate malignancy risk (relative to benign/borderline ovarian lesions). Biologically, we documented dominance of pro-tumorigenic, myeloid si-NFκB responseHIGHsi-IFN/ISG responseLOW inflammation in periphery of patients with OV. Finally, in an orthotopic murine metastatic OV model, sFIS assay predicted the higher capacity of chemo-immunotherapy (paclitaxel-carboplatin plus anti-TNF antibody combination) in achieving a pro-immunogenic peripheral milieu (si-IFN/ISG responseHIGHsi-NFκB responseLOW), which aligned with high antitumor efficacy. CONCLUSIONS: We established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22011996
003      
CZ-PrNML
005      
20220506131509.0
007      
ta
008      
220425s2021 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1136/jitc-2021-003609 $2 doi
035    __
$a (PubMed)34795003
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Sprooten, Jenny $u Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
245    10
$a Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer / $c J. Sprooten, A. Vankerckhoven, I. Vanmeerbeek, DM. Borras, Y. Berckmans, R. Wouters, RS. Laureano, T. Baert, L. Boon, C. Landolfo, AC. Testa, D. Fischerova, C. Van Holsbeke, T. Bourne, V. Chiappa, W. Froyman, D. Schols, P. Agostinis, D. Timmerman, S. Tejpar, I. Vergote, A. Coosemans, AD. Garg
520    9_
$a BACKGROUND: Tumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers' detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification. METHODS: We used a data-driven in silico framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and whole-blood immune cell counts. Here, sFIS assay's ability to determine survival benefit or malignancy risk was validated in a discovery (n=32) and/or validation (n=699) patient cohorts. Lastly, we used an orthotopic murine metastatic OV model, with anti-OV therapy selection via in silico drug-target screening and murine serum screening via sFIS assay, to assess suitable in vivo immunotherapy options. RESULTS: In silico data-driven framework predicted that peripheral immunodynamics of patients with cancer might be best captured via analyzing myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) signaling and interferon-stimulated genes' (ISG) responses. This helped in conceptualization of an 'in sitro' (in vitro+in situ) sFIS assay, where human myeloid cells were exposed to patients' serum in vitro, to assess serum-induced (si)-NFκB or interferon (IFN)/ISG responses (as active signaling reporter activity) within them, thereby 'mimicking' patients' in situ immunodynamic status. Multiparametric serum profiling of patients with OV established that sFIS assay can: decode peripheral immunology (by indicating higher enrichment of si-NFκB over si-IFN/ISG responses), estimate survival trends (si-NFκB or si-IFN/ISG responses associating with negative or positive prognosis, respectively), and coestimate malignancy risk (relative to benign/borderline ovarian lesions). Biologically, we documented dominance of pro-tumorigenic, myeloid si-NFκB responseHIGHsi-IFN/ISG responseLOW inflammation in periphery of patients with OV. Finally, in an orthotopic murine metastatic OV model, sFIS assay predicted the higher capacity of chemo-immunotherapy (paclitaxel-carboplatin plus anti-TNF antibody combination) in achieving a pro-immunogenic peripheral milieu (si-IFN/ISG responseHIGHsi-NFκB responseLOW), which aligned with high antitumor efficacy. CONCLUSIONS: We established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.
650    _2
$a zvířata $7 D000818
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a imunoterapie $x metody $7 D007167
650    _2
$a myši $7 D051379
650    _2
$a NF-kappa B $x metabolismus $7 D016328
650    _2
$a nádory vaječníků $x farmakoterapie $x genetika $x mortalita $7 D010051
650    _2
$a analýza přežití $7 D016019
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Vankerckhoven, Ann $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium
700    1_
$a Vanmeerbeek, Isaure $u Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium $1 https://orcid.org/0000000158946008
700    1_
$a Borras, Daniel M $u Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
700    1_
$a Berckmans, Yani $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium $1 https://orcid.org/0000000313505596
700    1_
$a Wouters, Roxanne $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium
700    1_
$a Laureano, Raquel S $u Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
700    1_
$a Baert, Thais $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium $u Department of Oncology, Leuven Cancer Institute, Laboratory of Gynaecologic Oncology, KU Leuven, Leuven, Belgium
700    1_
$a Boon, Louis $u JJP Biologics, Warsaw, Poland
700    1_
$a Landolfo, Chiara $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium $u Department of Development and Regeneration, KU Leuven, Leuven, Belgium $u Queen Charlotte's and Chelsea Hospital, Imperial College, London, UK $u Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
700    1_
$a Testa, Antonia Carla $u Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy $u Dipartimento Scienze della Vita e Sanità pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
700    1_
$a Fischerova, Daniela $u Charles University, Praha, Czech Republic
700    1_
$a Van Holsbeke, Caroline $u Ziekenhuis Oost-Limburg, Genk, Belgium
700    1_
$a Bourne, Tom $u Queen Charlotte's and Chelsea Hospital, Imperial College, London, UK
700    1_
$a Chiappa, Valentina $u National Cancer Institute of Milan, Milan, Italy
700    1_
$a Froyman, Wouter $u Department of Development and Regeneration, KU Leuven, Leuven, Belgium $u Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium
700    1_
$a Schols, Dominique $u Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium
700    1_
$a Agostinis, Patrizia $u Department of Cellular and Molecular Medicine, Cell Death Research and Therapy Laboratory, KU Leuven, Belgium $u VIB Center for Cancer Biology, VIB, Leuven, Belgium
700    1_
$a Timmerman, Dirk $u Department of Development and Regeneration, KU Leuven, Leuven, Belgium $u Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium
700    1_
$a Tejpar, Sabine $u Laboratory for Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
700    1_
$a Vergote, Ignace $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium $u Department of Oncology, Leuven Cancer Institute, Laboratory of Gynaecologic Oncology, KU Leuven, Leuven, Belgium $u Department of Gynaecology and Obstetrics, UZ Leuven, Leuven, Belgium
700    1_
$a Coosemans, An $u Department of Oncology, Leuven Cancer Institute, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium $1 https://orcid.org/0000000273214339
700    1_
$a Garg, Abhishek D $u Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium abhishek.garg@kuleuven.be $1 https://orcid.org/0000000299769922
773    0_
$w MED00201262 $t Journal for immunotherapy of cancer $x 2051-1426 $g Roč. 9, č. 11 (2021)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34795003 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220425 $b ABA008
991    __
$a 20220506131501 $b ABA008
999    __
$a ok $b bmc $g 1789542 $s 1163197
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 9 $c 11 $e - $i 2051-1426 $m Journal for immunotherapy of cancer $n J Immunother Cancer $x MED00201262
LZP    __
$a Pubmed-20220425
Zpět

Najít záznam

Citační ukazatele

Možnosti archivace