Fig. 8: Slc4a4 targeting overcomes immunotherapy resistance.

a, MFI of PD-1 in CD8⁺ T cells in sgNT (n = 5, 6 and 12) and sgSlc4a4 (n = 5, 7 and 12) subcutaneous Panc02 (left) and orthotopic KPC₁ (middle) and KPC₃ tumors (right). b, MFI of CTLA-4 in Foxp3⁺ T cells in sgNT (n = 6, 6 and 8) and sgSlc4a4 (n = 6, 7 and 8) subcutaneous Panc02 (left) and orthotopic KPC₁ (middle) and KPC₃ tumors (right). c, MFI of PD-L1 in CD45^– cells in sgNT (n = 6, 6 and 8) and sgSlc4a4 (n = 6, 7 and 8) subcutaneous Panc02 (left) and orthotopic KPC₁ (middle) and KPC₃ tumors (right). d, Growth of sgNT and sgSlc4a4 subcutaneous Panc02 tumors treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 6, sgNT-anti-PD-1/anti-CTLA-4 n = 6, sgSlc4a4-IgG n = 6, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 5). e, Weight of sgNT and sgSlc4a4 subcutaneous Panc02 tumors treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 11, sgNT-anti-PD-1/anti-CTLA-4 n = 9, sgSlc4a4-IgG n = 9, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 9). f, Survival curve of sgNT and sgSlc4a4 subcutaneous Panc02 tumor-bearing mice treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 8, sgNT-anti-PD-1/anti-CTLA-4 n = 7, sgSlc4a4-IgG n = 7, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 8). g, Weight of sgNT and sgSlc4a4 orthotopic KPC₁ tumors treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 9, sgNT-anti-PD-1/anti-CTLA-4 n = 8, sgSlc4a4-IgG n = 9, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 8). h, Survival curve of sgNT and sgSlc4a4 orthotopic KPC₁ tumor-bearing mice treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 8, sgNT-anti-PD-1/anti-CTLA-4 n = 8, sgSlc4a4-IgG n = 8, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 8). i, Survival curve of sgNT and sgSlc4a4 orthotopic KPC₁ tumor-bearing mice treated with anti-PD-1 (sgNT-IgG n = 9, sgNT-anti-PD-1 n = 9, sgSlc4a4-IgG n = 9, sgSlc4a4-anti-PD-1 n = 9). j, Survival curve of sgNT and sgSlc4a4 orthotopic KPC₁ tumor-bearing mice treated with anti-CTLA-4 (sgNT-IgG n = 8, sgNT-anti-CTLA-4 n = 8, sgSlc4a4-IgG n = 8, sgSlc4a4-anti-CTLA-4 n = 8). k, Weight of sgNT and sgSlc4a4 orthotopic KPC₃ tumors treated with anti-PD-1 and anti-CTLA-4 (sgNT-IgG n = 16, sgNT-anti-PD-1/anti-CTLA-4 n = 14, sgSlc4a4-IgG n = 14, sgSlc4a4-anti-PD-1/anti-CTLA-4 n = 14). Data in e and k are representative of a pool of two independent experiments. Treatment regimen is indicated by the arrows (mice were treated three times per week with up to six injections; d, f and h–j). P value was assessed by unpaired, two-tailed Student’s t-test (a–c), two-way ANOVA with Sidak’s multiple comparison test (d), two-way ANOVA with Tukey’s multiple comparison test (e, g and k) and log-rank (Mantel–Cox) test (f and h–j). Graphs show mean ± s.e.m.

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