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EP39664
Abstract: Objectives:
PD1 and PD-L1 are surface molecules located on T cells and cancer cells (and APC), correspondently. When Immunological Synapse (IS) is formed between the cells PD-L1 is able to bind to PD1, thereby stimulating inhibitory signaling in T cells which results in suppression of T cell proliferation. There were several studies ([PMID: 12517932], [PMID: 11015443], [PMID: 11857337]) where authors measured proliferating response of T cells in vitro as function of varying amount of PD-L1 immobilized on the surface of the beads/microspheres added to the T cells. Basing on the experimental results we can identify total amount of PD-L1 located on the all beads/microspheres added to the test tube corresponding to half maximal inhibition of T cell proliferation. But the value does not allow us to understand how many PD1-PDL1 complexes should be formed in IS to provide half maximal suppression of T cell proliferation.
In this study we will estimate IC50 and Imax characterizing effect of PD1-PDL1 complex on T cell proliferation. For the purposes we use in vitro experimental data measured for human CD4 T cells published in [PMID: 12517932].
Methods:
Estimation of the parameters will be performed in several consecutive steps:
(1) Calculation of number of PD-L1.Fc attached to microspheres,
(2) Calculation of number of PD1-PDL1 complexes in IS formed by T cells and microspheres with different PD-L1 density,
(3) Estimation of IC50 and Imax basing on values calculated in clauses (1) and (2).
Dependence of apparent proliferation rate constant on PD1-PDL1 complex was described in accordance with approach presented in [1]:
k_pro = kbase_pro*(1 + Imax*PD1_PDL1/IC50)/(1 + PD1_PDL1/IC50)
To calculate number of PD1-PDL1 complexes in IS we have used a rate law describing binding of surface molecules in IS derived in [2]. To calculate the values of IC50 and Imax we have used description of T cell proliferation entitled as “generation dependent proliferation” (see [3]).
Results:
Application of the workflow and methods described above allows us to come to following estimates:
IC50 = 812 PD1-PDL1 complexes per IS
Imax < 0.06
Conclusions:
Basing on previously derived rate law describing binding of surface molecules in immunological synapse and in vitro experimental data describing effect PD1-PDL1 complex on T cell proliferation, we have estimated IC50 and Imax quantifying the suppression effect of PD1-PDL1 complex.
Summary: Basing on previously derived rate law describing binding of surface molecules in immunological synapse and in vitro experimental data describing effect PD1-PDL1 complex on T cell proliferation, we have estimated IC50 and Imax quantifying the suppression effect of PD1-PDL1 complex.References: [1] https://insysbio.com/blog/an-approach-to-describe-multiple-effects-of-cytokines-on-cell-dynamics-processes
[2] https://insysbio.com/blog/derivation-of-rate-law-describing-binding-of-surface-molecules-in-immunological-synapse
[3] https://drive.google.com/file/d/15qMMMfC0dN_U1zBmtetRAKVNygSMdTke/view
PD1 and PD-L1 are surface molecules located on T cells and cancer cells (and APC), correspondently. When Immunological Synapse (IS) is formed between the cells PD-L1 is able to bind to PD1, thereby stimulating inhibitory signaling in T cells which results in suppression of T cell proliferation. There were several studies ([PMID: 12517932], [PMID: 11015443], [PMID: 11857337]) where authors measured proliferating response of T cells in vitro as function of varying amount of PD-L1 immobilized on the surface of the beads/microspheres added to the T cells. Basing on the experimental results we can identify total amount of PD-L1 located on the all beads/microspheres added to the test tube corresponding to half maximal inhibition of T cell proliferation. But the value does not allow us to understand how many PD1-PDL1 complexes should be formed in IS to provide half maximal suppression of T cell proliferation.
In this study we will estimate IC50 and Imax characterizing effect of PD1-PDL1 complex on T cell proliferation. For the purposes we use in vitro experimental data measured for human CD4 T cells published in [PMID: 12517932].
Methods:
Estimation of the parameters will be performed in several consecutive steps:
(1) Calculation of number of PD-L1.Fc attached to microspheres,
(2) Calculation of number of PD1-PDL1 complexes in IS formed by T cells and microspheres with different PD-L1 density,
(3) Estimation of IC50 and Imax basing on values calculated in clauses (1) and (2).
Dependence of apparent proliferation rate constant on PD1-PDL1 complex was described in accordance with approach presented in [1]:
k_pro = kbase_pro*(1 + Imax*PD1_PDL1/IC50)/(1 + PD1_PDL1/IC50)
To calculate number of PD1-PDL1 complexes in IS we have used a rate law describing binding of surface molecules in IS derived in [2]. To calculate the values of IC50 and Imax we have used description of T cell proliferation entitled as “generation dependent proliferation” (see [3]).
Results:
Application of the workflow and methods described above allows us to come to following estimates:
IC50 = 812 PD1-PDL1 complexes per IS
Imax < 0.06
Conclusions:
Basing on previously derived rate law describing binding of surface molecules in immunological synapse and in vitro experimental data describing effect PD1-PDL1 complex on T cell proliferation, we have estimated IC50 and Imax quantifying the suppression effect of PD1-PDL1 complex.
Summary: Basing on previously derived rate law describing binding of surface molecules in immunological synapse and in vitro experimental data describing effect PD1-PDL1 complex on T cell proliferation, we have estimated IC50 and Imax quantifying the suppression effect of PD1-PDL1 complex.References: [1] https://insysbio.com/blog/an-approach-to-describe-multiple-effects-of-cytokines-on-cell-dynamics-processes
[2] https://insysbio.com/blog/derivation-of-rate-law-describing-binding-of-surface-molecules-in-immunological-synapse
[3] https://drive.google.com/file/d/15qMMMfC0dN_U1zBmtetRAKVNygSMdTke/view
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