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Fig. 6 | Journal for ImmunoTherapy of Cancer

Fig. 6

From: Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies

Fig. 6

MEDI9197 enhances expression of PD1/L1 and increases immune stimulatory and anti-tumor effects of PD-L1 blockade. a and b The tumor immune profile was evaluated by qPCR following IT dosing. B16-OVA tumors were collected 3, 7, and 11 days post IT dose (20 μg MEDI9197 or Vehicle, n = 5). Total RNA was processed from each tumor, as described in Fig. 5a. The data indicate fold-change in gene expression associated with (a) Inhibitory and Checkpoint, and (b) Co-stimulatory genes. Fold-change is relative to the Vehicle group. Day 6–11 post MEDI9197 treatment results are enriched for responders. Multiple T tests were performed using dCT values to compare MEDI9197 treated versus Vehicle group (a, b). c-d Percentage of PD-1+ and/or PD-L1+ populations from tumor cells, TILs (CD45+) (c), and effector CD8α+ cells (CD45+/TCRβ+/CD8α+/CD44+/CD62L) (d) measured by flow cytometry in tumors 6–8 days post-dose of MEDI9197 (n = 11) or Vehicle (n = 7). Statistical analysis used 2-way ANOVA with Tukey’s multiple comparisons test (c) and Mann-Whitney test (unpaired, non-parametric t test) (d). Data is representative of at least two independent experiments. e Kaplan-Meier plots of survival in the B16-OVA tumor model following MEDI9197 and anti-PD-L1 treatment. C57BL/6 albino mice (n = 10/group) were implanted SC in the right flank with B16-OVA tumors on day 0. On day 10, mice were dosed IT with 20 μg MEDI9197 or Vehicle, and twice weekly for 6 doses IP with 200 μg of anti-PD-L1 Ab or isotype control. CR, complete responder. Statistical analysis was performed using the Log-rank (Mantel-Cox) test. f Cytokine production after 3 (IL-2) and 5 (IFNγ) days of co-culture of allogeneic T cells with human Mo-DCs (10:1 ratio). DCs were primed for 18 h with a titration of MEDI9197 before medium change and addition of T cells plus 100 nM Durvalumab or NIP228 isotype control. Data are representative of 4 donors and statistical analysis was performed using two-way ANOVA with Bonferroni post-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

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