SYSTEMS AND METHODS FOR ASSESSING MODULATORS OF IMMUNE CHECKPOINTS

1 . A composition comprising an artificial antigen presenting cell (aAPC) or phospholipid droplet displaying on its surface a T cell receptor (TCR) activator and an immune checkpoint ligand (ICL).

2 .- 3 . (canceled)

4 . The composition of claim 1 , wherein the TCR activator is an anti-cluster of differentiation 3 (CD3) antibody, or an antibody fragment thereof, or major histocompatibility complex (MHC).

5 . The composition of claim 1 , wherein the ICL is selected from the group consisting of PD-L1, PD-L2, B7-H4, CD155, galectin-9, and HVEM.

6 . (canceled)

7 . A system comprising:

(a) an effector cell displaying on its surface an immune checkpoint receptor (ICR), and comprising a T cell receptor (TCR); and

(b) an artificial antigen presenting cell (aAPC) or phospholipid droplet displaying on its surface a T cell receptor (TCR) activator and an immune checkpoint ligand (ICL);

wherein the ICR and ICL form an ICR/ICL complex upon interaction.

8 . The system of claim 7 , wherein formation of the ICR/ICL complex results in modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways.

9 . The system of claim 8 , wherein modulation comprises:

(a) inhibition of TCR activation by the TCR activator and/or one or more TCR-dependent pathways; or

(b) enhancement of TCR activation by the TCR activator and/or one or more TCR-dependent pathways.

10 . The system of claim 7 , wherein the TCR activator is an anti-cluster-of-differentiation-3 (CD3) antibody, or an antibody fragment thereof, or major histocompatibility complex (MHC).

11 . The system of claim 7 , wherein the ICL is selected from the group consisting of CD80/86 PD-L1, PD-L2, B7-H4, CD155, galectin-9, and HVEM.

12 . The system of claim 7 , wherein the ICR is selected from the group consisting of PD-1, CTLA-4, LAG-3, TIM-3, CD160, TIGIT, IL-10 receptor, and BTLA.

13 . The system of claim 7 , wherein the effector cell is selected from T cells including Jurkat, HuT-78, CEM, Molt-4 and primary T cells.

14 . The system of claim 7 , wherein the effector cell further comprises a reporter of: TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

15 .- 16 . (canceled)

17 . The system of claim 14 , wherein the reporter is a natural reporter, intrinsic to the effector cell type, having a characteristic that is detectable and correlates to TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

18 . The system of claim 14 , wherein the reporter is an artificial reporter, exogenous to the effector cell type, having a characteristic that is detectable and correlates to TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

19 . The system of claim 18 , wherein the reporter is a gene, the expression of which is under the control of TCR-pathway-dependent reporter.

20 . The system of claim 19 , wherein the TCR-pathway-dependent reporter is a nuclear factor of activated T cells (NFAT) promoter.

21 . (canceled)

22 . The system of claim 7 , further comprising a blockade agent or test blockade agent.

23 . The system of claim 22 , wherein the blockade agent inhibits formation of the ICR/ICL complex, resulting in modulation of TCR activation or TCR pathway activation.

24 .- 28 . (canceled)

29 . A method comprising:

(a) forming a system comprising:

(i) an effector cell displaying on its surface an immune checkpoint receptor (ICR), and comprising a T Cell Receptor (TCR) and a TCR-pathway-dependent reporter, and

(ii) an artificial antigen presenting cell (aAPC) displaying on its surface a TCR activator and an immune checkpoint ligand (ICL); wherein the ICR and ICL form an ICR/ICL complex upon interaction, and wherein formation of the ICR/ICL complex results in modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways; and

(b) detecting said TCR-pathway-dependent reporter or a signal from said reporter.

30 . The method of claim 29 , further comprising adding to the system a blockade agent, wherein the blockade agent inhibits formation of the ICR/ICL complex or inhibits ICR/ICL-dependent modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways.

31 . The method of claim 30 , wherein said TCR-pathway-dependent reporter or a signal from said reporter is detected: (1) before, (2) concurrent with, and/or (3) after addition of said blockade agent, and further comprising a step of comparing signal from (1) before, (2) concurrent with, and/or (3) after addition of said blockade agent to determine the effect of the blockade agent.

32 .- 39 . (canceled)