A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model
Abstract
:1. Introduction
2. Results
2.1. MIM-3 Acts as an Immune-Modulator of Cytokines’ Secretion in Macrophages Cultivated under Various Immune Contexts
2.2. MIM-4 Displays Slight Anti-Proliferative Effects on Colon Carcinoma Cells Cultivated in 2-Dimensions, under Starvation
2.3. MIM-4 Displays Moderate Anti-Proliferative Effects on Colon Carcinoma Cells Cultivated in a 3-Dimensions-Spheroids’ Model
2.4. MIM-seq Displays Slight Anti-Tumor Effects in an In Vivo Subcutaneous Xenograft Model of Colon Carcinoma
2.5. MIM-4 Could Act as an Adjuvant When Associated with Etoposide or Resveratrol, in an In Vitro 3D-Spheroid Model of Colorectal Cancer
3. Discussion
4. Materials and Methods
4.1. Tested Item and Experimental Control
4.2. Phagocytosis
4.3. Macrophage Cytokine Secretion Evaluation
4.4. Colon Cancer In Vitro Models
4.4.1. Experiments Performed on Classical Monolayer Cultured HCT-116 Cells
4.4.2. Initiation of the Spheroid Model
4.4.3. Kinetics of 3D Spheroid Growth and Cytotoxicity
4.4.4. Data Analysis
4.5. Colon Cancer Animal Model
4.5.1. Animal Housing and General Experimental Conditions
4.5.2. Cell Culture for the Generation of the In Vivo Model
4.5.3. In Vivo Study Design
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
2D: | 2-dimensions |
3D: | 3-dimensions; |
AA: | amino acids; |
AMPK: | AMP-activated protein kinase; |
BSA: | bovine serum albumin; |
CH: | centesimal Hahnemannian |
COX: | cyclooxygenase |
CRC: | colorectal cancer; |
CTLs: | cytotoxic T lymphocytes; |
DNA: | deoxyribonucleic acid |
EGF: | epidermal growth factor; |
EGFR: | epidermal growth factor receptor |
ELISA: | enzyme linked immunosorbent assay; |
EMA: | European Medicines Agency; |
ETP: | etoposide; |
FBS: | fetal bovine serum; |
FCS: | fetal calf serum; |
FDA: | Food and Drug Administration; |
FGF2: | fibroblast growth factor 2; |
fMLP: | N-formyl methionyl-leucyl-phenylalanine; |
GFI: | green fluorescence integral; |
GFP: | green fluorescent protein; |
GM-CSF: | granulocyte-macrophage colony-stimulating factor; |
H&E: | hematoxylin and eosin; |
HLA: | human leukocyte antigen; |
hr: | human recombinant; |
IFN: | interferon; |
IHC: | immunohistochemistry; |
ILs: | interleukins; |
K: | Korsakovian dilution; |
LD: | low dose; |
LPS: | lipopolysaccharide; |
M1: | M1 macrophage; |
MCH: | major histocompatibility complex; |
M-CSF: | macrophage colony-stimulating factor; |
MI: | micro-immunotherapy; |
MIM: | micro-immunotherapy medicine; |
NF-κB: | nuclear factor kappa-light-chain-enhancer of activated B cells; |
NGFI: | normalized green fluorescence intensity; |
NK: | natural killer; |
NMRI: | naval medical research institute; |
NO: | nitric oxide; |
PBMCs: | peripheral blood mononuclear cells; PBS: Phosphate buffer saline; |
PFA: | Paraformaldehyde; |
P/S: | penicillin/streptomycin; |
RNA: | ribonucleic acid; |
ROS: | reactive oxygen species; |
RSV: | resveratrol; |
RT: | room temperature; |
SIRT1: | silent mating type information regulator two homolog 1; |
SKP: | serial kinetic process; |
SNA®: | specific nucleic acids; |
TAMs: | tumor-associated macrophages; TARC: thymus and activation-regulated chemokine; |
TGF-β: | transforming growth factor-β; |
TGFBR: | transforming growth factor receptor; |
TLR: | toll-like receptor; |
TNF-α: | tumor necrosis factor-α; |
TUNEL: | terminal deoxynucleotidyl transferase dUTP nick end labeling; |
ULD: | ultra-low dose; |
VEGF: | vascular endothelial growth factor; |
Veh: | vehicle; |
Wnt: | wingless-related integration site; |
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MIM-seq Composition | MIM-3 Composition | MIM-4 Composition |
---|---|---|
hr-IL-1β (9 CH) | - | - |
hr-IL-2 (3 CH) | hr-IL-2 (3 CH) | - |
hr-IL-6 (9 CH) | - | - |
hr-IL-7 (4 CH) | - | - |
hr-IL-10 (27 CH) | hr-IL-10 (27 CH) | - |
hr-IL-12 (4 CH) | hr-IL-12 (4 CH) | hr-IL-12 (4 CH) |
hr-IFN-α (3 CH) | hr-IFN-α (3 CH) | - |
hr-IFN-γ (6 CH) | hr-IFN-γ (6 CH) | - |
hr-TNF-α (5 CH) | - | hr-TNF-α (5 CH) |
h-EGF (27 CH) | - | h-EGF (27 CH) |
h-bFGF (27 CH) | - | - |
hr-IGF-1 (27 CH) | hr-IGF-1 (27 CH) | - |
hr-TGF-β (27 CH) | - | hr-TGF-β (27 CH) |
DNA (6-12-30-200 K) | - | DNA (6–12 K) |
RNA (6-12-30-200 K) | RNA (30–200 K) | - |
SNA®-C1a01 (18 CH) | - | SNA®-C1a01 (18 CH) |
SNA®-C1b01 (18 CH) | - | SNA®-C1b01 (18 CH) |
SNA®-C1c01 (18 CH) | - | SNA®-C1c01 (18 CH) |
SNA®-HLA I (18 CH) | SNA®-HLA I (18 CH) | - |
SNA®-HLA II (18 CH) | - | - |
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Jacques, C.; Marchesi, I.; Fiorentino, F.P.; Chatelais, M.; Lilli, N.L.; Appel, K.; Lejeune, B.; Floris, I. A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model. Int. J. Mol. Sci. 2022, 23, 6059. https://doi.org/10.3390/ijms23116059
Jacques C, Marchesi I, Fiorentino FP, Chatelais M, Lilli NL, Appel K, Lejeune B, Floris I. A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model. International Journal of Molecular Sciences. 2022; 23(11):6059. https://doi.org/10.3390/ijms23116059
Chicago/Turabian StyleJacques, Camille, Irene Marchesi, Francesco Paolo Fiorentino, Mathias Chatelais, Nicoletta Libera Lilli, Kurt Appel, Beatrice Lejeune, and Ilaria Floris. 2022. "A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model" International Journal of Molecular Sciences 23, no. 11: 6059. https://doi.org/10.3390/ijms23116059