Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. In Vitro Assay
2.1.1. Specimens
2.1.2. SSTR Expression in Peripheral Blood
2.1.3. Intracellular IL-2 and IFNg Expression
2.1.4. Apoptosis Assay
2.1.5. Transcription Factor Assays
2.2. In Vivo Analyses
2.2.1. Patient Selection Criteria
2.2.2. Treatment Response
2.2.3. Treatment Schedule
2.2.4. Sorting of T Cell Subpopulations for NanoString Analysis
2.2.5. NanoString Assay
2.2.6. Statistical Analysis of NanoString Data
3. Results
3.1. In Vitro Results
3.1.1. SSTR Expression on T Cells
3.1.2. In Vitro Effects of Lanreotide on T Cell Function and Survival
3.2. In Vivo Results
3.2.1. Patient Characteristics
3.2.2. Proteomic and Transcriptional Analysis of T Cells of NET Patients in Relation to Lanreotide Response
3.2.3. Treatment Response Effect
3.2.4. Treatment Effect
3.2.5. Interaction Effect
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Healthy Donor T Cell Phenotyping | ||||
---|---|---|---|---|
Antigen | Fluor | Clone | Vendor | Cat # |
CD3 | APCH7 | SK7 | BD Pharmingen | 560176 |
CD4 | PECy7 | SK3 | BD Pharmingen | 557852 |
CD8 | PerCP | SK1 | BD Biosciences | 347314 |
CD25 | PE | 2A3 | BD Biosciences | 341009 |
CD127 | BV421 | HIL-7R-M21 | BD Horizon | 562436 |
SSTR expression | ||||
Rb anti-SSTR1 | N/A | UMB7 | Abcam | ab137083 |
Ms anti-SSTR2 | N/A | 402038 | Biotechne | MAB4224 |
Rb anti-SSTR3 | N/A | UMB5 | Abcam | ab137026 |
Rb anti-SSTR4 | N/A | Polyclonal | Abcam | ab28578 |
Ms anti-SSTR5 | N/A | 394401 | Biotechne | MAB4448 |
Dky anti Rb IgG | AF647 | N/A | Jackson ImmunoResearch | 711-605-152 |
Gt anti Ms. IgG | AF647 | N/A | Jackson ImmunoResearch | 115-605-003 |
Cytokine expression | ||||
IL-2 | APC | 5344.111 | BD FastImmune | 341116 |
IFN-γ | BV510 | B27 | BD Horizon | 563287 |
Transcription Factor signaling | ||||
NFAT1 | N/A | D43B1 | Cell Signaling | 5861 |
NF-κB p65 | N/A | D14E12 | Cell Signaling | 8242 |
ERK1/2 | N/A | 137F5 | Cell Signaling | 4695 |
NanoString antibodies | ||||
CD3 | FITC | UCHT1 | Biolegend | 300406 |
CD8 | PerCPCy5.5 | HIT8a | Biolegend | 300924 |
CD4 | BV510 | A161A1 | Biolegend | 357420 |
CD25 | PE | BC96 | Biolegend | 302606 |
CD127 | PECy7 | A019D5 | Biolegend | 351320 |
LiveDead | Violet | N/A | ThermoFisher | L23105 |
NFAT1 | Lanreotide (µM) | NFAT1 Baseline Mean SS (SE) | NFAT1 PMA/Ion Mean SS (SE) | NFAT1 CD3/CD28 Mean SS (SE) |
---|---|---|---|---|
T-helper | 0 | 0.06 (0.04) | 2.54 (0.07) | 0.42 (0.05) |
0.5 | 0.04 (0.04) | 2.69 (0.05) | 0.42 (0.05) | |
5 | 0.09 (0.06) | 2.66 (0.05) | 0.40 (0.06) | |
T-cytotoxic | 0 | −0.04 (0.05) | 2.58 (0.08) | 0.36 (0.06) |
0.5 | −0.06 (0.05) | 2.68 (0.06) | 0.33 (0.05) | |
5 | −0.03 (0.05) | 2.68 (0.05) | 0.34 (0.06) | |
Treg | 0 | 0.26 (0.04) | 2.52 (0.07) | 0.60 (0.05) |
0.5 | 0.23 (0.05) | 2.67 (0.05) | 0.56 (0.06) | |
5 | 0.25 (0.05) | 2.60 (0.05) | 0.56 (0.07) | |
NF-κB/p65 | Lanreotide (µM) | NF-κB/p65 Baseline Mean SS (SE) | NF-κB/p65 PMA/Ion Mean SS (SE) | NF-κB/p65 CD3/CD28 Mean SS (SE) |
T-helper | 0 | 0.25 (0.12) | 2.04 (0.15) | 1.04 (0.05) |
0.5 | 0.25 (0.11) | 2.04 (0.13) | 0.98 (0.07) | |
5 | 0.16 (0.12) | 2.07 (0.14) | 1.05 (0.07) | |
T-cytotoxic | 0 | 0.15 (0.12) | 1.94 (0.12) | 0.86 (0.07) |
0.5 | 0.14 (0.10) | 1.92 (0.13) | 0.83 (0.08) | |
5 | 0.05 (0.12) | 1.97 (0.13) | 0.86 (0.09) | |
Treg | 0 | 0.50 (0.14) | 2.13 (0.13) | 1.26 (0.07) |
0.5 | 0.53 (0.10) | 2.09 (0.12) | 1.18 (0.10) | |
5 | 0.41 (0.14) | 2.12 (0.14) | 1.24 (0.09) | |
ERK1/2 | Lanreotide (µM) | ERK1/2 Baseline Mean SS (SE) | ERK1/2 PMA/Ion Mean SS (SE) | ERK1/2 CD3/CD28 Mean SS (SE) |
T-helper | 0 | 1.12 (0.04) | 1.44 (0.07) | 1.17 (0.03) |
0.5 | 1.10 (0.05) | 1.51 (0.07) | 1.22 (0.03) | |
5 | 1.15 (0.04) | 1.47 (0.06) | 1.20 (0.03) | |
T-cytotoxic | 0 | 1.02 (0.05) | 1.39 (0.09) | 1.10 (0.07) |
0.5 | 0.98 (0.05) | 1.47 (0.08) | 1.09 (0.05) | |
5 | 1.05 (0.05) | 1.42 (0.09) | 1.06 (0.05) | |
Treg | 0 | 1.33 (0.05) | 1.53 (0.06) | 1.37 (0.04) |
0.5 | 1.32 (0.05) | 1.61 (0.07) | 1.40 (0.04) | |
5 | 1.38 (0.06) | 1.60 (0.07) | 1.37 (0.03) |
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Responders (N = 9) | Non-Responders (N = 8) | |
---|---|---|
Age Median (range), y | 69 (34–79) | 66 (50–81) |
Origin | ||
pNET | 5 | 4 |
Intestinal NET | 4 | 3 |
Unknown | 0 | 1 |
Metastatic sites, N | ||
Liver | 6 | 6 |
Nodes | 1 | 2 |
Lung | 0 | 1 |
Skin | 0 | 1 |
Peritoneum | 1 | 0 |
Ki 67, N | ||
Not specified | 1 | 2 |
<3% | 5 | 0 |
3–20% | 3 | 4 |
>20% | 0 | 2 |
Differentiation, N | ||
Not specified | 1 | 0 |
Well-differentiated | 8 | 7 |
Moderately differentiated | 0 | 1 |
Patient Effect | Treatment Effect | Interaction Effect | ||||||
---|---|---|---|---|---|---|---|---|
Tc | Th | Treg | Tc | Th | Treg | Tc | Th | Treg |
IRAK2 | POU2F2 | IGF1R | CCRL2 | LAG3 | MAP2K1 | CCRL2 | IL5RA | HLA_DRB3 |
TXNIP | TNFRSF14 | ECSIT | BCL2L1 | MS4A1 | PDCD1 | TNFRSF13C | IRAK2 | IRF5 |
IL6 | NUP107 | CCND3 | FCGR2A | TFEB | KIR_Inhibiting _Subgroup_1 | HLA_DRB4 | IFI16 | FCER1G |
TRAF6 | ATG5 | ITGA4 | MRC1 | CASP3 | EP300 | IRAK2 | NUP107 | MFGE8 |
VEGFC | TFEB | C1QBP | TLR6 | EGR1 | TP53 | FEZ1 | C1QBP | ATF2 |
SPA17 | IL21R | RELA | KLRC2 | GTF3C1 | NFKBIA | TXNIP | LAG3 | HLA_DPB1 |
KLRC2 | CREB1 | MERTK | CLEC4C | BCL10 | FCER1G | CMKLR1 | BID | LAMP3 |
SIGIRR | AKT3 | CD7 | HLA_DRB4 | PSMD7 | CD80 | CDKN1A | BCL10 | KIR_Inhibiting _Subgroup_1 |
TNFSF12 | IL17RA | CREB1 | CD79B | TRAF6 | TYK2 | CLEC4A | PSMD7 | PDCD1 |
TNFRSF13C | TXNIP | TXNIP | MASP1 | XCL2 | HLA_DPB1 | MICA | MS4A1 | IGF1R |
CREB1 | GZMK | LAMP3 | NFKBIA | DDX58 | CCR2 | TMEFF2 | TXNIP | TNFRSF10C |
MAP2K4 | BCL2 | PIN1 | TLR8 | NFKBIA | NUP107 | CD70 | CCL4 | RELA |
CD3E | CASP3 | CXCR5 | TNFRSF13C | CXCR6 | SH2D1A | FAS | TRAF6 | EP300 |
MIF | MAP2K1 | ITGAL | DMBT1 | CD3EAP | TFRC | TNFRSF12A | CXCR3 | TXNIP |
FOS | HLA_DPB1 | BCL2 | LILRB1 | CR1 | CCR9 | TRAF6 | JAM3 | IL13 |
CARD11 | ATM | SMAD3 | YTHDF2 | IRAK2 | IL8 | FOXJ1 | IL18RAP | ECSIT |
ITGB2 | IRAK4 | CARD11 | IL6ST | IL5RA | TLR10 | TNFSF13 | NOTCH1 | IL1R1 |
IL11 | CD40LG | TCF7 | FUT7 | CXCL5 | IRF5 | IFIT1 | PTGDR2 | SPACA3 |
SMAD3 | ITGAL | RUNX1 | MAP2K4 | EOMES | MFGE8 | IFIH1 | TNFRSF14 | XCR1 |
FAS | PSMB9 | IRAK4 | KIR3DL2 | S100A8 | IL6ST | LILRB1 | GTF3C1 | BCL10 |
Pathway | NES | p Adjusted | |
---|---|---|---|
Patient Effect | |||
Th | NOD-like receptor signaling pathway | −1.527 | 0.0469 |
Yersinia infection | −1.594 | 0.0369 | |
Herpes simplex virus 1 infection | −1.624 | 0.0208 | |
Human immunodeficiency virus 1 infection | −1.628 | 0.0234 | |
Regulation of actin cytoskeleton | −1.780 | 0.0208 | |
Tc | - | ||
Treg | - | ||
Treatment Effect | |||
Th | Cell surface interactions at the vascular wall | 1.705 | 0.0354 |
Disease | −1.386 | 0.0354 | |
RNA Polymerase II Transcription | −1.580 | 0.0354 | |
Generic Transcription Pathway | −1.610 | 0.0326 | |
Gene expression (Transcription) | −1.652 | 0.0203 | |
Cellular responses to stress | −1.780 | 0.0203 | |
Cellular responses to stimuli | −1.780 | 0.0203 | |
Deubiquitination | −1.844 | 0.0345 | |
Post-translational protein modification | −1.852 | 0.0184 | |
Purinergic signaling in leishmaniasis infection | −1.867 | 0.0394 | |
Cell recruitment (pro-inflammatory response) | −1.867 | 0.0394 | |
Metabolism of RNA | −1.892 | 0.0203 | |
Metabolism of proteins | −1.902 | 0.0054 | |
Ub-specific processing proteases | −1.908 | 0.0203 | |
Tc | Metabolism of proteins | −1.765 | 0.0485 |
cGMP-PKG signaling pathway | 1.833 | 0.0234 | |
Ras signaling pathway | 1.817 | 0.0234 | |
Focal adhesion | 1.746 | 0.0432 | |
Rap1 signaling pathway | 1.716 | 0.0493 | |
Cell adhesion molecules | 1.678 | 0.0432 | |
Yersinia infection | 1.663 | 0.0432 | |
T cell receptor signaling pathway | 1.662 | 0.0432 | |
PI3K-Akt signaling pathway | 1.632 | 0.0432 | |
Treg | - | ||
Interaction Effect | |||
Th | - | ||
Tc | Signaling by TGF-beta Receptor Complex | 2.003 | 0.0438 |
Signaling by TGFB family members | 2.003 | 0.0438 | |
Treg | Host Interactions of HIV factors | 1.693 | 0.0171 |
HIV Infection | 1.683 | 0.0171 | |
TCF dependent signaling in response to WNT | 1.681 | 0.0171 | |
Cell surface interactions at the vascular wall | 1.651 | 0.0171 | |
TCR signaling | 1.638 | 0.0276 | |
Signaling by ROBO receptors | 1.622 | 0.0350 | |
Signaling by WNT | 1.608 | 0.0350 | |
Transcriptional regulation by RUNX3 | 1.581 | 0.0350 | |
Diseases of signal transduction by growth factor receptors and second messengers | 1.548 | 0.0350 | |
Generic Transcription Pathway | 1.503 | 0.0276 | |
RNA Polymerase II Transcription | 1.469 | 0.0350 | |
Gene expression (Transcription) | 1.459 | 0.0469 |
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Alaklabi, S.; Maguire, O.; Pattnaik, H.; Zhang, Y.; Chow, J.; Wang, J.; Minderman, H.; Iyer, R. Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors. Cancers 2024, 16, 3104. https://doi.org/10.3390/cancers16173104
Alaklabi S, Maguire O, Pattnaik H, Zhang Y, Chow J, Wang J, Minderman H, Iyer R. Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2024; 16(17):3104. https://doi.org/10.3390/cancers16173104
Chicago/Turabian StyleAlaklabi, Sabah, Orla Maguire, Harsha Pattnaik, Yali Zhang, Jacky Chow, Jianmin Wang, Hans Minderman, and Renuka Iyer. 2024. "Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors" Cancers 16, no. 17: 3104. https://doi.org/10.3390/cancers16173104