Extended Data Fig. 7. Targeting HDAC2 and inhibiting PD-L1 deacetylation can enhance immunotherapy efficacy.

a, b, Tumour growth (a) and survival curves (b) of nude mice bearing MC 38 tumors treated with control antibody, PD-1 mAb, HDAC2 inhibitor or combined therapy. c, TILs from treated MC38 syngeneic tumours (Control, n=6; PD-1 mAb, n=8; HDAC2i, n=6; Combined, n=8) after stimulation were analyzed for Interferon γ (IFNγ), IL-2 and IL-10. d, Immunofluorescence for PD-L1 and DAPI of MC38 syngeneic tumours treated as indicated. Scale bars, 10 μm. n=4 independent samples per group. e, f, Tumour growth (e) and survival curves (f) of BALB/c mice bearing tumor derived from CT26-Pd-l1 KO cells with re-introduced WT or K262Q Pd-l1, treated with control antibody or PD-1 mAb. Tumour volume was shown as mean ± s.d. Statistics in e, two-tailed Student’s t-test. g, Tumour growth of MC38/K262Q Pd-l1 tumour-bearing C57BL/6 mice treated as indicated. h, A schematic diagram of molecular mechanism underling nuclear translocation of PD-L1 and its contradictory functions in immune response. PD-L1 deacetylated by HDAC2 is translocated into the nucleus via interacting with various key regulatory proteins for endocytosis and nuclear translocation, then transactivates immune responsive in the nucleus to impact tumour sensitivity to PD-1 blockage (the lower left panel with yellow background), as well as controlling various immune checkpoint gene expression to possibly confer resistance to PD-1 blockage treatment (the lower right panel with gray background). Thus, HDAC2 inhibitor will reduce PD-L1 nuclear localization to prevent the emerging resistance to PD-1 blockade treatment. P values in b and f were calculated using Gehan-Breslow-Wilcoxo test, two-sided. Statistical source data are available in Statistical Source Data Extended Data Fig. 7.