Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Influence Network: Proliferation, Survival, and Differentiation of T Cells Downstream of TCR Signalling
2.2. Logical Model of TCR Network
2.3. Model Validation. Simulations of Different Aspects of T Cell Biology
2.4. Role of Individual Inhibiting Immune Checkpoint Receptors in TCR Signalling Modulation
2.5. Two-Step Simulations of T Cell Response in Cancer Treated with PD1 and CTLA4 Inhibitors
2.6. Comparison of the Model Simulations with Experimental Observations
2.7. Role of Cytokines in the Modulation of the Effect of the Checkpoint Therapy
3. Discussion
4. Materials and Methods
4.1. Construction of the Network of the Immune Checkpoint Inhibitor Response
4.2. Logical Modelling and Simulations
4.3. Model Simulation of Immune Checkpoint Inhibiting Treatments
4.4. Model Accessibility and Data Availability
4.5. Data Used for Experimental Validation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Conditions | Initial Conditions |
---|---|
1. Role of individual inhibiting immune checkpoint receptors in TCR signalling modulation | CD80/86 (ligand for CTLA4 or CD28) only |
PD1_L (ligand for PD1) only | |
LAG3_L (ligand for LAG3) only | |
TIM3_L (ligand for TIM3) only | |
TIGIT_L (ligand for TIGIT or CD226) only | |
2. Priming in lymph node (LN) vs. secondary tumour microenvironment (TME) activation (two-step process) | LN (immune checkpoints active): CTLA4, ICOS, TNFRs |
TME (immune checkpoints active): ICOS, TNFRs, PD1, TIGIT, LAG3, TIM3 | |
3. CD8+ vs. CD4+ cells | CD8+ (ligands): MHCI |
CD4+ (ligands): MHCII |
Cell Population | Type of ICI Therapy | T Cell Proliferation | Th1_Cytotoxicity | Treg | |||
---|---|---|---|---|---|---|---|
Model | Experimental Data (Different Methods) | Model | Experimental Data IFNG/pTbet/GZMB (Granzyme B) | Model | Experimental Data ** Treg Ratio/IL10/TGFβ | ||
All TILs | anti-CTLA4 | NA | ↑ | ↑/NA/NA | ↓ | No effect/No effect/- - | |
All TILs | anti-PD1 (anti PD1-L) | NA | ↑ | ↑/NA/NA | ↓ | ↓/↓/↓ | |
All TILs | anti-CTLA4 & anti-PD1 | NA | ↑↑ | ↑↑/NA/NA | ↓↓ | ↓↓/↓/↓↓ | |
(anti-CTLA4 & anti PD1-L) | |||||||
CD8+ (total) | Anti-CTLA4 | ↑ (clonal expansion in LN) | ↑ | ↑ | ↑/↑/↑ | NA | |
CD8+ (total) | anti-PD1 (anti-PD1-L) | ↑ (effect in the TME) | ↑ (↑) | ↑ | ↑/↑/↑ | NA | |
(↑/↑↑/↑) | |||||||
CD8+ (total) | anti-CTLA4 & anti-PD1 | ↑↑ | ↑↑ | ↑↑ | ↑↑/↑/↑↑ | NA | |
(anti PD1-L) | (↑↑) | (↑↑/↑↑/↑↑) | |||||
CD8+ PD1+CTLA4− | anti-CTLA4 | no effect * | no effect | NA | NA | ||
CD8+ PD1+CTLA4− | anti-PD1 | ↑ | ↑ | NA | NA | ||
CD8+ PD1+CTLA4− | anti-CTLA4 & anti-PD1 | ↑ * (same effect as anti-PD1 alone) | ↑ | NA | NA | ||
CD8+ PD1+CTLA4+ | anti-CTLA4 | ↑ | ↑ | NA | NA | ||
CD8+ PD1+CTLA4+ | anti-PD1 | ↑ | ↑ | NA | NA | ||
CD8+ PD1+CTLA4+ | anti-CTLA4 + anti-PD1 | ↑↑ | ↑↑ | NA | NA |
Therapy | LN: Proliferation | LN: Th1_CTL/Treg Ratio | TME: Proliferation | TME: Th1_CTL/Treg Ratio | Clinical Outcome: (Patients Survival) [5] |
---|---|---|---|---|---|
anti-CTLA4 | ↑ | ↑ | no effect | no effect | ↑ |
anti-PD1 | no effect | no effect | ↑ | ↑ | ↑↑ |
anti-PD1+anti-CTLA4 | ↑ | ↑ | ↑ | ↑ | ↑↑↑ |
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Kondratova, M.; Barillot, E.; Zinovyev, A.; Calzone, L. Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response. Cancers 2020, 12, 3600. https://doi.org/10.3390/cancers12123600
Kondratova M, Barillot E, Zinovyev A, Calzone L. Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response. Cancers. 2020; 12(12):3600. https://doi.org/10.3390/cancers12123600
Chicago/Turabian StyleKondratova, Maria, Emmanuel Barillot, Andrei Zinovyev, and Laurence Calzone. 2020. "Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response" Cancers 12, no. 12: 3600. https://doi.org/10.3390/cancers12123600