Fig. 2: TIGIT disruption increases T cell avidity and recover degranulation capacity of low-avidity T cells. | Nature Communications

Fig. 2: TIGIT disruption increases T cell avidity and recover degranulation capacity of low-avidity T cells.

From: TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength

Fig. 2: TIGIT disruption increases T cell avidity and recover degranulation capacity of low-avidity T cells.

A Killing capacity of TAA-TCR edited T cells cocultured at 5:1 effector-to-target ratio with BxPC3-A2+ (antigen positive, HLA-A*0201 positive) PDAC cell line. Antigen low/negative or HLA-A*0201 negative cell lines were used as controls. N = 3 biological independent samples for each TCR. B Avidity of TAA-TCR edited T cells on K562-A2+ leukemic cell line pulsed with 10 μg/ml of each specific peptide (left). Statistical analysis was performed on the max curvature point of AGR2 avidity curve (dotted line, right). N = 3 matched biological independent samples for each TCR. Statistical analysis by paired two-tailed t test. C, D Functional avidity of TCRKO DKK1- and MSLN-specific T cells indicated as the co-expression of CD107a, IFNγ, IL-2, and TNFα after a 6 h co-culture with T2 cells loaded with decreasing concentrations of each specific peptide or an unrelated one as control. n°(0-4) indicates the number of co-expressed molecules. N = 3 biological independent samples for MSLN-specific T cells, n = 2 biological independent samples for DKK1-specific T cells. E Simultaneous editing efficiency of the endogenous TCR and TIGIT by BE4max evaluated at day 15 after T cell activation. Editing efficiency is indicated as frequency of C•G-to-T•A conversion at the target base in TRAC, TRBC1, TRBC2 and TIGIT (left) and as reduction of CD3 and TIGIT surface expression in multiplex edited T cells (edited) compared to untreated T cells (UT, right). N = 6 biological independent samples. F Expansion of total viable TCRKOTIGITKO + TCR and TCRKOTIGITCOMP + TCR T cells. Untreated T cells were used as control (left). N = 3 matched biological independent samples. Relative distribution of stem memory (TSCM; CD45RA+CD62L+), central memory (TCM; CD45RA-CD62L+), effector memory (TEM; CD45RA-CD62L-), and terminally differentiated effector (TEMRA; CD45RA+CD62L-) cells for each T cell group (right). N = 6 matched biological independent samples. G Avidity of TCRKOTIGITKO and TCRKOTIGITCOMP MSLN-specific T cells (top) and DKK1-specific T cells (bottom) measured as in (B). N = 2 biological independent samples for MSLN-specific T cells, n = 3 biological independent samples for DKK1-specific T cells. Statistical analysis by paired two-tailed t-test. H Functional avidity of TCRKOTIGITKO and TCRKOTIGITCOMP MSLN-specific T cells (top) and DKK1-specific T cells (bottom) measured as in (C, D). The dotted line represents the smallest significant value of TCRKOTIGITCOMP DKK1-specific T cells when compared to its control. N = 3 biological independent samples for each TCR specificity. Data are represented as mean ± s.e.m. Statistical analysis performed by two-way ANOVA unless otherwise stated. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Source data and exact p values are provided as a Source Data file.

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